mitochondria as target for antiischemic drugs

Advanced Drug Delivery Reviews 49 (2001) 151–174www.elsevier.com/ locate /drugdeliv

Mitochondria as target for antiischemic drugsa , b c a*Didier Morin , Thierry Hauet , Michael Spedding , Jean-Paul Tillement

a ´ ´Laboratoire de Pharmacologie and Centre National de La Recherche Scientifique, Faculte de Medecine de Paris XII,´8 rue du General Sarrail, F-94010 Creteil, France

b ´ ´ `Unite de Transplantation Expetimentale, INRA le Magneraud, Surgeres, FrancecInstitut de Recherches Internationales Servier (IRIS), 192 avenue Charles de Gaulle, 92200 Neuilly sur Seine, France

Accepted 5 February 2001

Abstract

The cessation of blood flow followed by a reperfusion period results in severe damages to cell structures. This induces a1complex cascade of events involving, more particularly, a loss of energy, an alteration of ionic homeostasis promoting H

21and Ca build up and the generation of free radicals. In this context, mitochondria are highly vulnerable and play apredominant role in the cell signaling leading from life to death. This is why, recently, efforts to find an effective therapy forischemia–reperfusion injury have focused on mitochondria. This review summarizes the pharmacological strategies whichare currently developed and the potential mitochondrial targets which could be involved in the protection of cells. 2001Elsevier Science B.V. All rights reserved.

21Keywords: Ischemia; Reperfusion; Ca overload; Antioxidant; Mitochondrial transition pore; Mitochondrial metabolism

Contents

1. Introduction ............................................................................................................................................................................ 1522. Cellular events mediated by ischemia–reperfusion..................................................................................................................... 153

2.1. Ischemia.......................................................................................................................................................................... 1532.2. Reperfusion ..................................................................................................................................................................... 154

3. Pharmacological strategies to protect cells from ischemia–reperfusion injury............................................................................... 1543.1. Modulation of mitochondrial metabolism........................................................................................................................... 154

3.1.1. Direct effects ......................................................................................................................................................... 1563.1.1.1. Trimetazidine ............................................................................................................................................ 1563.1.1.2. Ranolazine ................................................................................................................................................ 1563.1.1.3. Dichloroacetate ......................................................................................................................................... 1563.1.1.4. Carnitine palmitoyltransferase (CPT) inhibitors ........................................................................................... 1573.1.1.5. Coenzyme Q ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15710

3.1.1.6. Other modulators....................................................................................................................................... 1581 213.1.2. Indirect effects: the Na /Ca exchanger inhibitors ................................................................................................. 158

213.2. The inhibition of Ca overload ........................................................................................................................................ 15813.2.1. Mitochondrial K channel openers .......................................................................................................................... 158

*Corresponding author. Tel.: 133-1-4981-3661; fax: 133-1-4981-3594.E-mail address: [email protected] (D. Morin).

0169-409X/01/$ – see front matter 2001 Elsevier Science B.V. All rights reserved.PI I : S0169-409X( 01 )00132-6

152 D. Morin et al. / Advanced Drug Delivery Reviews 49 (2001) 151 –174

3.2.2. Uncoupler agents ................................................................................................................................................... 1593.3. The antioxidant strategy ................................................................................................................................................... 160

3.3.1. Ginkgo biloba ...................................................................................................................................... 1603.3.2. Trans-resveratrol.................................................................................................................................................... 1613.3.3. Propofol ................................................................................................................................................................ 1613.3.4. Nitrones ................................................................................................................................................................ 1623.3.5. Carvedilol.............................................................................................................................................................. 1623.3.6. Ebselen ................................................................................................................................................................. 1623.3.7. Coenzyme Q and idebenone ................................................................................................................................. 16210

3.4. The permeability transition pore (PTP) as a pharmacological target ..................................................................................... 1633.4.1. The effects of cyclosporin A (CsA) ......................................................................................................................... 1633.4.2. Coenzymes Q ........................................................................................................................................................ 1643.4.3. Other pharmacological inhibitors............................................................................................................................. 165

4. Metabolic diseases, ischaemia and stress: interactions with mitochondria .................................................................................... 1655. The particular case of the preserving solutions for organ transplantation...................................................................................... 1656. Conclusions ............................................................................................................................................................................ 166References .................................................................................................................................................................................. 167

1. Introduction clinical efficacy, especially in the field of the neuro-protection. Several reasons have been invoked to

There are increasing amount of recent evidences explain this failure but the main is probably that allthat mitochondria are involved in the molecular these compounds are capable of inhibiting a specificevents leading to the tissue damage occurring in event of the ischemic cascade but not to protectdifferent physio-pathological situations like is- entirely the cells. To solve this problem, a promisingchemia, neurodegenerative diseases and basically in way would be to combine therapy and thus to act onthe ageing process itself [1–3]. This is particularly different targets during the same treatment. Astrue for ischemia which is characterized by an underlined by De Keyser et al. [4], this approachinterruption of blood flow and thus, causes a reduc- would require research conditions unavailable now,tion of oxygen availability for the cell. In the for example, agreement between pharmaceuticalabsence of oxygen supply, mitochondrial respiration companies and/or ability to test molecules which areis prevented and ATP synthesis altered. The rupture not effective on their own. Nevertheless, the worksof the ionic homeostasis induces a depolarization and of Biegon and Bar Joseph [5] and of Chabrier et al.an accumulation of toxic concentrations of calcium [6] are derived from this idea. They developedin the cytosol. This is why most of the pharmaco- interesting molecules which associate two potentiallogical strategies have tried to search for chemical protective activities, an antioxidant and a NMDAagents able to reduce this ionic disturbance. This antagonism in the first case, an antioxidant and a NOgave birth to a wide variety of compounds which synthase inhibitor effect in the second case.protect central or peripheral cells in different animal Recently, new therapeutic approaches have fo-models of ischemia: the drugs include calcium entry cused on mitochondrial protection. Several reasons

1blockers, Na channel inhibitors, N-methyl-D-aspar- justify this approach. First, whatever the type oftate receptor /channel (NMDA) and a-amino-3-hy- ischemia considered, peripheral or central, the phys-droxy-5-methyl-4-isoxazolepropanoic acid (AMPA) iological events have a common final consequence,receptor antagonists, inhibitors of glutamate release the alteration of the mitochondrial functions. Second,and enhancers of the activity of GABA. Another mitochondria is the major provider of energy in theapproach was to inhibit the activation of NO synth- cell and it is essential to preserve this function duringase and to scavenge free radical oxygen species an episode of ischemia followed or not by a period(ROS). of reperfusion. Third, mitochondria control intracel-

Although many efforts have been made to develop lular calcium and upon stress generate a high quanti-new drugs, none of them has demonstrated a proven ty of ROS, two key elements which play a crucial

D. Morin et al. / Advanced Drug Delivery Reviews 49 (2001) 151 –174 153

role in the evolution of the cell injuries. Fourth, these supply to the cell. The resulting hypoxia preventsorganelles have been recently shown to coordinate, oxidative phosphorylation and, consequently, inducesat least in part, cellular events leading to apoptosis a rapid reduction of the ATP concentration availableand/or necrosis with the recent discovery that the in the cell, a transient rise in ADP which is degradedformation of a pore, generally named permeability and a massive accumulation of phosphate (Fig. 1).transition pore (PTP) may play a pivotal role in cell The failure of mitochondrial ATP synthesis is tempo-death [7,8]. rarily balanced by anaerobic glycolysis which

The aim of this study is to review briefly the produces lactate and causes a decrease of tissue pH.existing marketed antiischemic drugs showing a Glycogen depletion and lactate accumulation in-mitochondrial protecting activity and to discuss the crease as a function of the severity of ischemia.possible mitochondrial targets which could be in- When hypoxic conditions persist, the net decrease of

1 1volved in the protection of cells from ischemia– ATP concentrations inhibits Na /K ATPase lead-reperfusion injury. ing to a progressive increase of the concentration of

1cytosolic Na and a concomitant increase of ex-1 1 1 21tracellular K . Na , in turn, activates Na /Ca

1 12. Cellular events mediated by ischemia– and Na /H exchanges inducing an accumulation of21 1reperfusion Ca and protons. The intracellular Na rise results

in a depolarization of the cell membrane with212.1. Ischemia transient opening of the voltage-dependent Ca

21channel increasing Ca flux. In neurons, the entry1 21Ischemia corresponds to a reduction or a complete of cations (Na and/or Ca ) is also mediated by

blockade of blood flow in a tissue or in an organ (for the three major types of ionotropic glutamate re-reviews see Refs. [9,10]), with a rapid loss of oxygen ceptors N-methyl-D-aspartate, AMPA and kainic

Fig. 1. Scheme representing mitochondrial alterations during ischemia reperfusion. DC, mitochondrial membrane potential; PTP,permeability transition pore; RC, respiratory chain; ROS, radical oxygen species.


acid, which are activated by the release, and failure These pathological insults cause necrotic cellof reuptake, of excitatory amino acids, especially death but it has been increasingly recognized thatglutamate, in the synaptic cleft [11,12]. they can also induce apoptosis [23–26]. The nature

However, as the mitochondria are at least partially of the death would depend on the intensity of the21de-energized, mitochondrial Ca accumulation may insult and on the ability to maintain ATP synthesis.

not be severe. In the core of the infarct, cells rapidly loss ATP andTaken together, anaerobic glycolysis, nucleotide die by necrosis whereas peripheral cells continue to

hydrolysis and the release of protons from acidic produce ATP and are able to execute the apoptoticorganelle cause a drop of cytosolic pH by a unit or process [27], although in the CNS there is a spec-more [13]. This acidosis, associated with a low trum between the two modes of cell death, depend-

21mitochondrial Ca concentration, protects strongly ing on the cell type and local conditions [28].against the ischemic injury [14] and prevents theopening of the mitochondrial transition pore [15,16]although favorable opening conditions prevail (high 3. Pharmacological strategies to protect cellsPi, decrease ATP and ADP). However, prolongation from ischemia–reperfusion injuryof ischemia leads cells to a point of no return beyondwhich the cellular damages become irreversible and From mild to severe ischemia, the mitochondrialthe cell die. The length of the ischemic period to successive alterations include a deficit of the metabo-

21cause cell death depends on the organ and on the cell lism, an oxidative stress, a Ca overload, thetype. In the same way reperfusion corresponding to generation of the PTP leading to mitochondrialthe readmittance of oxygen to the cell can paradoxi- swelling and necrotic and/or apoptotic cell death. Ancally accelerate tissue necrosis [17]. increasing number of pharmacological approaches

are actually developed to try to interfere with these2.2. Reperfusion mitochondrial steps. They are briefly reviewed in this

section and summarized in Fig. 2.Reperfusion corresponds to the restoration of

oxygenated blood flow to the ischemic tissue. This 3.1. Modulation of mitochondrial metabolismsituation is encountered clinically in thrombolysis,by-pass surgery and organ transplantation. At the As mitochondrial alterations appear to determinemitochondrial level, it is characterized by the re- the progression of cell injury to a state of irrever-covery of the activity of the respiratory chain which sibility, the modulation of the mitochondrial metabo-restores the membrane potential and may drive the lism is the object of growing interest, especially forelevated cytosolic calcium into the mitochondria to cardiac ischemia. The aim of this approach is a bestthe detriment of ATP synthesis (Fig. 1) [18–20]. use of the available substrates during the ischemic

21Mitochondrial Ca overload per se is not a con- process to minimise the injury and to rescue tissues.dition which induces cell injury. Indeed, mitochon- This pharmacological strategy has been applied with

21dria are able to accumulate high Ca concentration success in the moderate or mild myocardial ischemiaif enough ATP and ADP are supplied and if matricial in Angina pectoris. The strategy is less effective inpyridine nucleotides are maintained in reduced state. the face of complete ischemia.However, the sudden influx of oxygen also leads to a In normoxic conditions, cardiac cells mainly useburst of ROS, which induces oxidative stress [21] the fatty acid pathway to generate ATP (70%) whenand deplete mitochondrial pyridine nucleotides and 30% comes from the utilization of glucose. Duringglutathione, reducing compounds protecting mito- ischemia nearly all ATP is produced by the oxidationchondria against oxidative insults. All these con- of fatty acids or by anaerobic pathways. Now theditions favour the mitochondrial pore opening which fatty acid pathway is less efficient (produced ATP/cause swelling, collapse of membrane potential and consumed oxygen55.2) than the glucidic one (ATP/in fine total inhibition of mitochondrial functions O56; [10]) and this contributes to increase the ATP[8,22]. deficit.


Fig. 2. Mitochondrial sites as targets for antiischemic drugs. 1, activating effect. 2, inhibiting effect; CPT, carnitine palmitoyltransferase;DCA, dichloroacetate; PDH, pyruvate dehydrogenase; PTP, permeability transition pore; ROS, radical oxygen species.

In addition, when ischemia pursues, the degra- accumulate are deleterious for the cell and secondlydation of fatty acid induces an accumulation of because the efficiency of ATP synthesis is low,acetylcoenzyme A which inhibits both pyruvate mitochondria consuming more oxygen to producedehydrogenase (PDH), the enzyme responsible for ATP than in normoxic conditions although thethe catabolism of pyruvate, and the enzymes of the quantity available is limited.beta-oxidation. This reinforces the inhibition of the Pharmacological approaches have been found toglucose pathway and increases the cytosolic accumu- redirect mitochondrial metabolism in order to favorlation of lactate and protons from pyruvate and thus glucose oxidation to the detriment to fatty acidthe acidosis. The levels of acylCoA and acylcarnitine catabolism. This would theoretically lead to a greateralso raise and they are deleterious for mitochondrial ATP/oxygen yield, a greater rate of pyruvate oxida-and plasma membranes [29]. tion and, thus, a decrease of lactate accumulation.

Thus, metabolic mitochondrial disorders are doub- This approach is particularly relevant for organsly baneful: First, because the lipid metabolites which using mainly fatty acid as a substrate. Several drugs,


i.e. etomoxir, ranolazine were developed according appears as a potential target for trimetazidine: fur-to this idea but up to now the only marketed drug thermore, enzyme inhibition is only partial so lipidavailable is trimetazidine. oxidation is not completely inhibited.

Whether this mechanism of action is relevant for3.1.1. Direct effects short or mild ischemia, it seems difficult to explain

entirely the pronounced protective effect we ob-3.1.1.1. Trimetazidine served after a total prolonged liver ischemia (2 h)

Trimetazidine (1-[2,3,4-trimethoxy-benzyl]piper- followed by 30-min reperfusion [34]. Other mecha-azine, 2 HCl) is registered since 1978 and marketed nisms have been suggested which include a reductionin a number of countries as a safe cellular anti- of ionic imbalance [39]. Indeed, we recently showedischemic drug devoid of hemodynamic effects. Al- that trimetazidine can cross cellular membranesthough the clinical efficacy of trimetazidine was transferring protons from an acidified cellular com-demonstrated in several double blind trials and its partment to the extracellular space [40].antianginal effect was shown to be equivalent to Altogether these data clearly indicate that mito-propranolol in a multicenter European trial (for a chondria is the main target of the drug. One canreview see Ref. [30]), the molecular mechanism of suppose that the overall protective effect correspondsits antiischemic effect was not fully understood until probably to a combination of the different propertiesrecently. Different hypotheses which are not mutual- of the drug according to the severity of the ischemia.ly exclusive have been proposed. A common featureof these hypothesis is that trimetazidine improves 3.1.1.2. Ranolazineenergy metabolism and ATP synthesis in different in Ranolazine has shown cardiac anti-ischemic ac-vitro and ex-vivo models of myocardial and liver tivity in several in vitro and in vivo animal modelsischemia [31–34]. One of them involves a switch of and antianginal properties in clinical trials [41,42]. Itthe cellular metabolism towards glucose utilization at does not affect hemodynamics or baseline contrac-the expense of lipid metabolism. This was suggested tion and, thus, like trimetazidine, offers the oppor-by the work of Fantini et al. [35] who showed that tunity to treat angina without reducing blood pres-trimetazidine was able to inhibit palmitoyl-carnitine sure, heart rate and myocardial contractility. Clarkeoxidation on rat cardiomyocytes. Identical results et al. [43] were the firsts to observe a prevention bywere found in ischemic isolated hearts perfused with the drug of the reduction in the amount of activefatty acid: trimetazidine reduced the deleterious PDH during the ischemic period. This protectiveincrease in acyl carnitine levels induced by ischemia effect was first thought to result from a direct action[36]. This effect is not due to a direct inhibition of of the drug on the enzyme but several studies failedpalmitoyl-carnitine transferase 1 (CPT-1), which to demonstrate any effect of the drug on PDH kinasetransports palmitoyl carnitine across mitochondrial or phosphatase, or on PDH catalytic activity [44]. Atmembranes, since trimetazidine was without effect the present time, the prevailing hypothesis is anon this enzyme [37]. On the other hand, tri- inhibition of fatty acid metabolism, probably partlymetazidine does not inhibit the accumulation of long by limiting the effect of palmitoyl-L-carnitine [45],chain acylCoA level. leading to a decrease of acetylCoA and an indirect

This reduction of fatty acids oxidation was associ- stimulation of PDH, a trimetazidine like profile.ated with a decrease in the activity of the long-chain Ranolazine is in phase III clinical trials as anisoform of the last enzyme involved in fatty acid antianginal agent and for the treatment of peripheraloxidation, 3-ketoacylcoenzyme A thiolase [38]. This arterial disease.effect occurred at low trimetazidine concentrations(IC 575 nM) and is accompanied by an increase in 3.1.1.3. Dichloroacetate50

glucose oxidation. This latter effect is not due to a Another way to promote carbohydrate oxidation isdirect enhancement of PDH activity but to a decrease to stimulate directly PDH. This enzyme is a complexof the inhibiting effect caused by the accumulation of protein including three major subunits that catalyzeacetylCoA. Thus, 3-ketoacylcoenzyme A thiolase the oxidation of pyruvate to acetylcoenzyme A. PDH


phosphatase dephosphorylates and stimulates the inhibitor 4-hydroxy-phenylglyoxylate. However,enzyme whereas PDH kinase inhibits it. Dich- long-term treatment with such drugs revealed aloroacetate inhibits PDH kinase and maintains PDH cardiotoxicity which hampered their clinical usein its active, phosphorylated form, enhancing pyru- [61]. A recent study reactivates this approach. In-vate oxidation [46,47]. The beneficial effect of deed, two well-known anti-anginal agents perhex-dichloroacetate can also be due to its ability to iline and amiodarone were shown to produce adecrease cytosolic acidosis that alters ionic homeo- concentration-dependent inhibition of CPT-1 [62].

21stasis and lead to Ca accumulation and mito- The IC of these drugs are relatively high, 77 and50

chondrial damage during reperfusion. Indeed, the 228 mM for perhexiline and amiodarone, respective-increase in pyruvate oxidation may promote lactate ly, but these drugs are known to be highly concen-elimination thereby increasing cellular pH. Such a trated in the tissues and particularly in mitochondriachange has been observed in patients during a [63,64]. So this effect is likely to contribute to thedichloroacetate treatment [48]. anti-ischemic effect of these two drugs and provide

The beneficial effect on ischemia and reperfusion an explanation for the ability of perhexiline tohas been demonstrated in isolated perfused rat heart decrease fatty acid oxidation in favor of glucose[49,50] and in the intact animal [51]. Few short-term oxidation, thereby increasing cardiac efficiency [65].clinical studies have been performed but they con-firmed the effectiveness of the drug in patients withmyocardial ischemia or heart failure [48,52,53]. 3.1.1.5. Coenzyme Q10

Clinical data indicate that the effect does not result Coenzymes Q are a group of lipid-soluble benzo-from an hemodynamic modification or an increase of quinones involved in the electron transport in mito-oxygen consumption but from an improvement of chondria. The endogenous occurring member issubstrate utilization. It should be noted that dich- coenzyme Q (ubiquinone 50) which is a lipid10

loroacetate also improved indices of both brain mobile constituent of the respiratory chain and actscerebral metabolism and neuronal and glial functions as an electron shuttle between complex I (oxidationin patients affected by various primary mitochondrial of NaDPH), complex II (oxidation of succinate) anddisorders [54]. Long-term clinical studies are lacking the cytochrome system of the complex III [66].but short-term administration appears to be safe. Exogenous administration of coenzyme Q was10

Unfortunately, the development of dichloroacetate is shown to improve myocardial functions in rats withlimited by a short half-life, and because high blood chronic heart failure [67] and during postischemicconcentrations (millimolar) are required to obtained reperfusion [68]. Coenzyme Q is an effective10

an effect and certainly also because it is not under blocker of lipid peroxidation but its protective mech-patent protection, as suggested by Stanley et al. [10]. anism during ischemia–reperfusion seems to be

mostly independent from this antioxidant effect.3.1.1.4. Carnitine palmitoyltransferase (CPT) in- Indeed, coenzyme Q neither scavenged the primary10

hibitors burst of superoxide or hydroxy radical generationAnother way explored to modulate mitochondrial when it was delivered immediately before reperfu-

metabolism is inhibition of CPT-1. This enzyme sion nor reduced the total free radical generationlocated on the mitochondrial outer membrane is during this period [69]. The protective effect of thisresponsible for long chain acyl carnitine formation. compound probably results from a multifactorialIts inhibition occurs upstream to the beta-oxidation, mechanism including a recovery of ATP and phos-reduces fatty acids oxidation and induces a sec- phocreatine concentrations initially and during re-ondary increase in glucose utilization [55,56]. This perfusion, and a protection of creatine kinase duringeffect protects heart from ischemic injury in vitro. reperfusion [69,70]. Coenzyme Q is commercial-10

This was demonstrated with the CPT-1 inhibitors ized as a drug in Japan and Italy and several studiesetomoxir [57], sodium 2-(5-(4-chlorophenyl)- have demonstrated clinical improvement in patientspentyl)-oxirane-2-carboxylate [58] and oxfenicine with congestive heart failure, ischemic heart disease[58–60] which is converted to the active CPT-1 and reperfusion injury [71,72].


213.1.1.6. Other modulators which regulate cellular Ca level. CGP37157A number of other compounds have been used to stimulated both the rate of NADH formation and

try to improve energy metabolism during ischemia. ATP production and these effects were directly1 21All are substrates or cofactors of key enzymes of the related to Na /Ca exchange inhibition [78]. How-

mitochondrial metabolism. The list includes L-car- ever, to our knowledge this elegant approach did notnitine, pyruvate, succinate, sulbutiamine, riboflavine, progress to a clinical study and has been abandonedthiamine and menadione (for reviews see Refs. [73– but CGP37157 remains a useful tool to study

2175]). Most of these drugs were shown to reduce Ca signal transmission in the cell.ischemic injury in a number of experimental modelsystems and may improve the clinical outcomes of

21patients. However, the potential utility and use of 3.2. The inhibition of Ca overloadthese therapeutic interventions is hampered by theabsence of serious controlled clinical trials. As discussed above, ischemia and more particu-

21larly reperfusion lead to a massive Ca accumula-1 213.1.2. Indirect effects: the Na /Ca exchanger tion which, under conditions of oxidative stress,

inhibitors culminates in an increase of membrane permeability21 21Ca enters mitochondria through an electropho- and an impairment of mitochondrial functions. Ca

retic uniporter that is driven by the inner membrane loading plays a crucial role in this phenomenon andpotential and is released by different ways involving its limitation represents a relevant objective. Con-

1 21 1 21two specific exchangers: Na /Ca and H /Ca . sistent with this hypothesis is the observation that1 21The major egress pathway is independent of Na in chelation of Ca or inhibition of mitochondrial

1 21non-excitable tissues while Na /Ca exchange uniporter by ruthenium red protects hearts againstpredominate in mitochondria from excitable tissues oxidant stress and ischemia–reperfusion injury [80–

21[76]. They maintain an appropriate Ca concen- 82]. Mitochondrial membrane potential is a criticaltration in the mitochondrial matrix. regulator of the mitochondrial capacity to accumulate

21 21Three Ca sensitive matrix dehydrogenases Ca and this prompted to consider the decrease ofmodulate mitochondrial metabolism, PDH, isocitrate the potential as a possible mechanism of cellularand alpha-ketoglutarate which both catalyse reactions protection. This profile of action is observed with

1within the Krebs cycle [77]. Within the range 0.2–2 K channel openers and uncoupler agents.ATP21

mM, Ca activates these enzymes and consequentlythe overall rate of ATP synthesis. Thus, increasing

1free matricial concentration might constitute another 3.2.1. Mitochondrial K channel openersway to improve energy metabolism and may be Inoue et al. [83] were the first to demonstrate the

1beneficial in some pathological situations as acute existence of K channels in the inner membrane ofATP

myocardial ischemia. This may be obtained by liver mitochondria (for recent reviews see Refs.21decreasing the efflux of Ca from mitochondria. [84,85]). These channels were found in heart and in

Such an approach was suggested 10 years ago [78]. brown adipose tissue and share some common21 1Certain Ca antagonists and benzodiazepines were properties with the sarcolemmal K channel. TheATP

1 21found to inhibit Na /Ca exchanger activity. Dil- channels have a pharmacological distinct profile.1tiazem and clonazepam were the most potent with 5-Hydroxydecanoate inhibited K flux in mitochon-

1IC values in isolated heart mitochondria in the mM dria but failed to block the sarcolemmal K50 ATP

range. This property has been suggested to play channel under any experimental conditions. In the1some role in the cardioprotective effect of the drug. same way, the K channel activator diazoxide isATP

According to this observation, Chiesi et al. [79] 2000-times more potent in opening the mitochondria1 1identified a new benzothiazepine CGP37157 which K channel than in opening the sarcolemma KATP ATP

was more potent (activity in the submicromolar channel [86].1range) and, especially more specific than the other The sole known function of the mitochondrial K

drugs, having no effect on the major mechanisms cycle is the regulation of the matrix volume [87].


1Mitochondrial K channels are regulated by sever- 3.2.2. Uncoupler agentsATP1Uncoupling is the result of an increase of the Hal endogenous compounds and recently, Hol-

permeability across the inner mitochondrial mem-muhamedov et al. [88] provide evidence that mito-1 brane. Uncoupling agents, such as 2-4-dinitrophenolchondrial K channel openers modulate functionsATP

(DNP) dissipate the proton gradient of the mitoch-vital for cardiac mitochondria. They demonstratedondrion and thus oxidative energy is wasted as heat.their implication in the induction of membraneDNP was used as a slimming aid in the 1930s. Fattydepolarization, the alleviation of ATP production, theacids, thyroid hormones and several synthetic com-induction of swelling and the release of accumulated

21 pounds are protonophorous uncouplers [96]. ThisCa and intermembrane proteins.effect is mediated by specialized proteins termedUsing diazoxide, Garlid et al. [89] observed auncoupling proteins which were first discovered incardioprotective effect of the drug in an isolated ratbrown adipose tissue (for review see Ref. [97]) andheart model of ischemia–reperfusion. This effect wasare responsible for thermogenesis, particularly duringcompletely abolished by the selective inhibitor 5-hibernation. Other proteins as the ADP/ATP antipor-hydroxydecanoate, excluding a role of the sarcolem-

1 ter (ANT) were also suggested to have uncouplingma K channel in ischemic protection. The cardio-ATPproperties.protective effect of diazoxide was confirmed in

A pronounced lasting uncoupling is baneful foranother model of ischemia [90,91] supporting themitochondria. Indeed, it was demonstrated to killhypothesis that cellular protection afforded by some

1 cells [98] and could be one of the components of theK openers may be mediated by their interactionmechanism of action of several anticancer drugswith mitochondria.causing PTP opening and apoptosis [99,100]. InDiazoxide restored myocardial ATP and creatineaddition, an increase of proton leak as well as anphosphate and attenuated the decrease in mitochon-inhibition of the respiratory chain have also been

drial oxygen consumption at the end of ischemia assuggested to contribute to ischemic heart alterations

well as at the end of the reperfusion [91].[101]. This might be caused by the generation of1How might opening of mitochondrial K channelsROS inducing damage to the mitochondrial mem-

protect the cell ? The beneficial effect could be the brane, especially complex I.1consequence of the net influx of K which causes a Meanwhile, recent data suggest that a mild uncou-partial dissipation of the membrane potential [92]. pling of mitochondria might be an interesting de-21This would prevent or release an excess of Ca fense strategy to limit the mitochondrial damageaccumulation [93]. However, activation of these generated by oxidative stress. This idea was de-channels was also shown to cause a decrease of ATP veloped by Skulachev’s group who demonstrated asynthesis and a release of cytochrome c in the close relationship between the mitochondrial mem-cytosol [88], two events which have been associated brane potential and ROS production [102]. Theywith the induction of apoptosis [8]. It should be also showed that a high transmembrane electrochemical

1noted that the membrane potential modulates PTP potential of H is dangerous for the cell since itopening [94] which is implicated in the pathogenesis increases the probability of ROS formation. Heof necrotic and apoptotic cell death [95]. proposed to induce a proton leak across the inner

The net mitochondrial effect of these drugs membrane in order to increase oxygen consumption(protective or deleterious) is therefore difficult to and thus to lower both the electrochemical potential

1predict but the convincing results obtained with of H and ROS production. A similar effect wasdiazoxide are very stimulating. Targeting mitochon- obtained by addition of malonate which inhibits

1drial K channel provides a useful approach to complex II and decreases the respiration rate [103],ATP

protect cells from disease conditions associated with indicating that both an increase or a decrease ofmetabolic alterations, especially ischemia–reperfu- oxygen consumption might inhibit ROS formation.sion. The development of this concept will need new This shows that ROS formation is function of thespecific agents to dissect the mechanism of cardiop- membrane potential rather than the electron transportrotection and to extend this research to other organs. rate in the respiratory chain and recent data support


the hypothesis that uncoupling proteins could reg- production since hypoxia slows down or stops theulate ROS generation [104]. electron transfer chain activity. This probably de-

Thus, mild uncoupling may represent an antiox- pends on its degree (complete or partial) and on itsygen defense mechanism during the reperfusion duration. Indeed, some in vitro studies [20,109]period, preventing the sudden increase of membrane clearly indicate that increasing the duration of is-

21potential but also limiting Ca entrance into mito- chemia reduces the protective mechanisms againstchondria. This is in line with the results of Nicholls oxygen toxicity (decrease SOD activity and GSHand Budd [105] who demonstrated that mitochon- content), with a concomitant increase in ROS pro-drial depolarization (and hence inhibition of mito- duction. This could be partly due to the slight rise of

21 21 21chondrial Ca accumulation) strongly protect cul- Ca occurring during hypoxia [19] since Catured cerebellar granule cells against glutamate toxic- potentiates ROS production [110].ity. Reperfusion amplifies the phenomenon and em-

In summary, a preventive mild uncoupling would phasizes mitochondrial alterations. As pointed outlimit the two principal deleterious mitochondrial before, the reactivation of the respiration at thephenomena occurring during ischemia-reperfusion, beginning of the postischemic reperfusion induces a

21 ?2Ca overload and ROS production. Actually, none burst of O which cannot be eliminated. In addition,221marketed drug fulfill these criteria but it is a promis- ROS production is exacerbated by Ca that ac-

ing field of research where uncoupling proteins cumulates during reperfusion [111,112]. ROS areappear as interesting targets. potentially very damaging for mitochondria causing

oxidation of lipids that could disturb the lipid bilayer3.3. The antioxidant strategy permeability essential for oxidative phosphorylation,

oxidation of proteins that could alter their activityMitochondria are the main site of free radical and oxidation of bases in mitochondrial DNA which

?production in the cell. This is a physiological event could modify its products. The radical hydroxyl OHunder aerobic conditions. ROS are mainly produced can generate toxic lipid peroxide products such asat the level of complex I and complex III of the malondialdehyde, 4-hydroxynonenal and can alsorespiratory chain [106]. In normal conditions only attack directly protein residues, like –SH groups,about 2–4% of the oxygen consumed is released in which have been involved in PTP opening [113]. Sothe mitochondrial matrix as a superoxide radical protecting mitochondria against the oxidative stress

?2 ?2(O ). O , following dismutation, can give birth to mediated by the ischemia–reperfusion is a major2 2?the radical hydroxyl (OH ) which is highly cytotox- objective. There are two main ways to protect

?2ic. Moreover, O can react with nitric oxide inside mitochondria against oxygen toxicity. The first one is2

mitochondria to yield damaging peroxynitrite. In to prevent the formation of ROS (see previousnormal conditions, ROS are eliminated by a very paragraph) but when it failed, the second wayefficient antioxidant system constituted by a group of consists in eliminating the toxic oxygen inter-enzymes, glutathione reductase (GR), glutathione mediates already formed. The next sections displayperoxidase (GP), superoxide dismutase (SOD) and natural and/or marketed compounds exhibiting thesethe NADPH transhydrogenase and vitamins C and E. properties.

The efficiency of these protecting systems declineswith age and as the leak of ROS from the respiratory 3.3.1. Ginkgo bilobachain is more pronounced (loss of electron transfer Ginkgo biloba extracts are obtained from the fruitschain activity), there is a general agreement to think and the leaves of the tree Ginkgo biloba and havethat the oxidative damages caused by ROS could be, been used therapeutically for centuries in traditionalat least in part responsible for ageing as well as for Chinese medicine. A highly refined extract (EGBneurodegenerative diseases [107,108]. Mitochondrial 761, bilobalide) has been used in France and inoxidative stress is also a major component of the Germany to treat peripheral vascular and neurologi-acute ischemia–reperfusion process. It is generally cal disorders since more than 20 years. Indeed, thisconsidered that ischemia does not promote ROS extract has been shown to have cardioprotective and


?2neuroprotective effects (for review see Refs. formation of O in a preparation of mitochondria2

[114,115]) and to be effective in the prevention of isolated from rat cerebral cortex. This effect was dueischemia–reperfusion injuries [116,117]. Its mecha- to the inhibition of complex III activity and morenism of action is not well-defined but it is evident specifically to an interaction with the de-now that some of its protective effect can be cylubiquinone cycle. It should be emphasized thatattributed to direct radical scavenging properties this effect is only partial (220% at 1 mM) and didsince bilobalide, which contains flavonoids, organic not suppress mitochondrial respiration whereas theacids and terpernoids, has been reported to scavenge total complex III blocker antimycin A stopped

2hydroxyl, superoxide, peroxyl and nitric oxide radi- oxygen consumption and amplified O production2

cals (for review see Ref. [118]). Recently, a mito- [129]. The fact that ROS are mainly generated atchondrial target was evoked to explain the beneficial complex III may explain why trans-resveratrol, byrole Ginkgo biloba against ischaemic injury. Seif-El- decreasing complex III activity, may limit the dam-Nasr and El-Fattah [119] demonstrated that Ginkgo age caused by ischemia–reperfusion. Therefore,biloba extract reduced the lipid peroxide and phos- trans-resveratrol combines two beneficial properties,pholipid content of rat brain mitochondria. In the a pure antioxidant and a mild uncoupling (inhibitionsame way Ginkgo biloba extract was shown to of complex III) activity. Trans-resveratrol was alsoprotect mitochondrial respiratory activity and to shown to inhibit ATPase activity [129]. This couldrestore oxidative phosphorylation efficiency impaired reinforced the beneficial effect of the drug sinceby hypoxia and anoxia / reoxygenation [120,121]. prevention of ATP depletion protects against cellThis effect may be due to the protection of complex I killing in different model of hypoxia or ischemiaactivity [122] which was related to the scavenging of [98,105,130].superoxide generated during the reoxygenation phase[121]. Indeed complex I activity declines duringischemia–reperfusion [123] and may result in an 3.3.3. Propofoloverproduction of free radicals as inhibition of Propofol is a general anesthetic which has acomplex I in vitro promotes free radical generation. chemical structure close to the nucleus of well-

In this hypothesis the antiischemic effect afforded known antioxidant substances as alpha-tocopherol. Itby bilobalide would be, at least in part, the conse- has been demonstrated to protect different tissuesquence of its antioxidant properties improving mito- from oxidative injury [131–133] and to be neuro-chondrial functions and aging [3]. and cardio-protective in several models of ischemia–

It must be underlined that bilobalide protects reperfusion [134–137]. The mechanism of protectionmitochondrial P450 side chain cleaving, the enzyme is attributable to the antioxidative property of prop-responsible for the cleavage of cholesterol to pre- ofol which is well established [138,139]. Erikssongnenolone, and regulates glucocorticoid synthesis [140] was the first to suggest that the protective[124,125]. This may also participate to its neuro- effect of propofol could be, at least in part, related toprotective mitochondrial effects. the protection of mitochondrial function. He showed

that propofol inhibited PTP opening in rat liver3.3.2. Trans-resveratrol mitochondria by scavenging free radicals. These

Trans-resveratrol is a phytoalexin found in various results were confirmed in a heart model of ischemia–plants and in some red wines. Its presence in these reperfusion: propofol conferred a significant protec-wines explains the apparent paradox of the beneficial tion and it was associated with a decrease of PTPeffect of long-term moderate wine intake in various opening [137,141]. However, its antioxidant activitypathological states including ischemic heart disease is probably not the only mechanism responsible for[126,127]. Its antioxidant properties are related to its PTP closure. Indeed, propofol has also a complexpolyphenol structure associated with a double bond uncoupler profile which probably contributes to the[128]. Trans-resveratrol is a free radical scavenger mitochondrial effect [142,143]. It is certainly anand is able to inhibit lipid peroxidation [129]. interesting drug that Javadov et al. [137] proposed toInterestingly, trans-resveratrol also prevented the add to cardioplegic solutions in heart surgery.


3.3.4. Nitrones release under conditions of ischemia–reperfusionNitrones have long been known to interact with [159]. This could also contribute to the protection of

mitochondria and modify cell function. Structure– the mitochondrial energetics during oxidative stress.activity of a series of nitrones at mitochondria was Thus, carvedilol is an original drug which joinsshown to correlate with smooth muscle relaxant together the classical property of a b-antagonisteffects [144], but nitrones have also recently been agent and an antioxidant activity associated withshown to have sufficiently powerful antiischaemic protection of mitochondrial functions.effects to merit testing in clinical trials. Nitrones mayfunction as spin traps of free radicals, and 2,29- 3.3.6. Ebselenpyridylisatogen (Fig. 3) [145] has been recently Another approach to assist the antioxidant defen-reported to form a highly stable adduct with free sive system is to activate the enzymes responsible forradicals [146]. This compound interferes with the ROS trapping or to mimic their effect. This ismitochondrial permability transition [147] and is achieved by ebselen (2-phenyl-1,2-benzisoselenazol-protective against glutamatergic-induced neural cell 3(2H )-one), a non-toxic seleno-organic drug withdeath in vivo (manuscript in preparation). Glutamate- antiinflammatory, antiatherosclerotic and cytoprotec-induced neuronal cell death requires mitochondrial tive properties that mimics the catalytic activities ofcalcium uptake [148] and the mitochondrial per- phospholipid hydroperoxide glutathione peroxidasemeability transition is a key factor (see below). Thus [160]. It has been shown to be a potent neuroprotec-nitrones may be powerful neuroprotective agents. In tive compound in stroke in humans [161] and inthis respect, N-t-butyl-a-phenyl-nitrone (tBPN) is a rodents [162,163] but also to prevent tissue injuriespotent spin trapping agent which is highly active in during heart [25], liver [164] and gastric [165]global and focal ischaemia models [149–151]. New ischemia–reperfusion. A microdialysis study indi-compounds such as NXY-059 are in evaluation for cates that ebselen limits cerebral metabolic changesuse in stroke [152]. during ischemia (decrease of lactate accumulation)

and accelerate the recovery during reperfusion [166].3.3.5. Carvedilol The effect of ebselen on mitochondria was little

Carvedilol is a vasodilating adrenoceptor antago- studied. Moreover, the agent was demonstrated tonist, possessing both a1- and b-adrenergic blocking protect liver mitochondria from lipid peroxidation,properties (for review see Ref. [153]), which protects induced by iron/ascorbate and iron/citratemyocardium against ischemic and lethal reperfusion [167,168]. This effect was associated with an inhibi-injury [154,155]. The drug also possesses antioxida- tion of the release of the apoptogenic factor cyto-tive properties [156] and has been shown to prevent chrome c [169] but does not seem to involve athe lipoperoxidation of mitochondrial membranes blockade of PTP opening [168,169] although oppo-[157]. In addition, carvedilol was recently shown to site results have been reported [170]. Altogetherinhibit NADH dehydrogenase [158], an enzyme these data suggest that the cytoprotective effect oflocated in the outer leaflet of the inner mitochondrial ebselen during ischemia–reperfusion may be due inmembrane, that has been shown to promote ROS part to its antioxidant properties at the mitochondrial

level.

3.3.7. Coenzyme Q and idebenone10

As specified before (Section 3.1.1.5.), the antiis-chemic properties of coenzyme Q were not consid-10

ered to result from its antioxidant effect. A derivativeof coenzyme Q, idebenone which is able to transferelectron inside the respiratory chain was also studied.In vitro and in vivo studies suggest the drug maydiminish nerve cell damage due to ischaemia, correct

Fig. 3. Structure of nitrone compounds. neurotransmitter defects and/or cerebral metabolism


and facilitate memory and learning [171]. However, these data. The idea is that if PTP is a key event inits development was stopped because it did not show the genesis of cell death following ischemia–reperfu-sufficient efficacy in the treatment of Alzheimer’s sion, molecules which are able to inhibit PTP woulddisease. probably help the cell to recover. CsA provided the

first evidence that this strategy is relevant.3.4. The permeability transition pore (PTP) as a It should be mentioned here that a recent observa-pharmacological target tion suggests that caspase-3 activity can be stimu-

lated directly in the first time of the ischemia beforePTP is a fast increase of permeability of the any detectable occurrence of PTP and any increase

mitochondrial membrane which causes membrane of caspase-9 activity, though located upstreamdepolarization, release of matrix molecules of molec- caspase-3 in the activation cascade [184]. This givesular mass less than 1500 Da, uncoupling oxidative another opportunity for a pharmacological interven-phosphorylation and swelling [7]. This phenomenon tion but this is not the subject of this review.was first described by Hunter and Haworth [172,173]and is now considered to be the consequence of the 3.4.1. The effects of cyclosporin A (CsA)formation of a pore. The first important step in the CsA was the first drug shown to inhibit PTP andcharacterization of PTP was the discovery that the up to now this is the most potent. It is generallyimmunosuppressant drug cyclosporin A (CsA) was assumed that CsA binds to a mitochondrial

21able to retain mitochondrial Ca [174] at very low cyclophilin (CyP-D) with nanomolar affinity andconcentrations and thus to inhibit PTP opening prevents the interaction of this protein with ANT[175]. The second one was the identification in the thus inhibiting pore opening [178,185].inner mitochondrial membrane of a high conductance Shortly after the identification of CsA as a PTPchannel whose opening appeared responsible for PTP inhibitor, several reports demonstrated that CsA[176]. prevented or delayed cell death in different models

Whereas a controversy persists concerning the of oxidative stress [186–188]. However, there wasmolecular composition of this pore, inner membrane no evidence of a direct link between the inhibition ofadenine nucleotide translocator (ANT) modulated by PTP and the protection of cells. Different eleganta cyclophilin (CyP-D) as suggested by Halestrap and approaches were used to address this question. First,Davidson [177] or multiproteic structure located at the immunosupressive effect of Csa was dissociatedthe level of the contact sites between the inner and from its mitochondrial interaction. A 4-substitutedthe outer mitochondrial membrane including porin, analogue of CsA lacking immunosuppressive proper-hexokinase, creatine kinase, ANT and CyP-D [178], ty (no inhibition of calcineurin) was shown to be asthere is now a good agreement to consider PTP as a active as CsA at inhibiting the pore [16]. Then,crucial event leading to cell death by necrosis or Lemasters’s group used laser scanning confocalapoptosis (for recent reviews, see Refs. [8,95,179]. microscopy to visualize the increase of mitochondrial

Crompton et al. [180] were the firsts to suggest membrane permeability within cells. Cells werethat PTP might be involved in the pathogenesis of loaded with fluorescent dyes which accumulatenecrotic cell death following ischemia–reperfusion. electrophoretically into mitochondria and provided aIndeed, they noticed that all cellular conditions good index of the membrane potential [189]. Hypo-

21which promote PTP (Ca overload, high Pi con- xia and oxidative stress caused a collapse of thecentrations, oxidative stress) prevail during is- potential as indicated by the modification of thechemia–reperfusion. This hypothesis was recently distribution of the dyes. CsA prevented these eventsreinforced when it was shown that PTP opening and protected the cells [190].might control apoptosis by causing release of apop- CsA also protected brain and heart from ischemia–togenic factors which activate caspases [181] and is reperfusion [191–193]. Griffiths and Halestrap [192]regulated by the pro- and the anti-apoptotic members have developed a perfusion technique using a radio-

3of the Bcl-2 family [182,183]. labelled marker [ H]2-deoxyglucose to monitor PTPA new pharmacological strategy appears from opening in the isolated rat heart during ischemia–


reperfusion. This study revealed that the pore re- of CsA may result from both PTP and non PTP-mained close during 30 min ischemia and open upon dependent mechanisms.reperfusion. Pretreatment of the organ with sub- However, both pharmacokinetic and pharmaco-micromolar concentrations of CsA prevented pore dynamic parameters argue against the clinical usedopening, improved the recovery of heart during of CsA in ischemia. The drug targets at least eightreperfusion but did not counteract the impairment of other cyclophilins in the cell whose roles are largelythe respiratory chain function as measured by the unknown and they are likely to bind most of theactivity of ATP synthase [192,194]. This alteration is drug. Thus, the mitochondrial concentration of CsAprobably due to the accumulation of ROS during is difficult to predict and a CsA treatment mayischemia and reperfusion [195]. require high, and even toxic, concentrations to reach

Taken together, these experiments established the mitochondrial target. In addition, the biotrans-clearly that PTP is a critical event in the genesis of formation of CsA may give birth to inactive metabo-cell injury generated by ischemia–reperfusion in lites towards PTP as observed with N-desmethyl-4-different peripheral organs and that CsA protects CsA [16].cells by inhibiting PTP during reperfusion. It does Moreover, in in vitro experiments, the protectingnot mean that other mechanisms are not involved in effect of CsA is only transient when mitochondrial

21the protective effect of CsA and this is particularly swelling is generated by Ca overload in theobvious in the brain where a definite role of PTP in presence of an oxidative stress. CsA slows down thecell death is less clear [196]. swelling but finally amplifies the phenomenon. Dif-

Consistent with the presence of PTP in brain are ferent hypothesis have been raised to explain thisthe experiments realized on isolated mitochondria deleterious effect [207,208] and there is good evi-[197,198], the observations that CsA delayed gluta- dence that CsA is able to cause oxidative stress inmate-induced mitochondrial depolarization [199] and cells [209].that its neuroprotective effect in a hypoglycemic rat So, CsA has been and remains a fantastic tool tomodel implicated PTP [200]. decorticate the biochemical mechanism of PTP and

However, strong evidences support the hypothesis provided new light on the sequence of events leadingthat the ability of CsA to protect neuronal cells does to ischemia–reperfusion injury. Its clinical use isnot result exclusively from inhibition of PTP. Indeed, difficult to consider in this indication but the search

21the Ca -calmodulin-dependent phosphatase cal- for more selective derivatives is probably the subjectcineurin might play a major role in the induction of of intensive work.neuronal death [201] and calcineurin inhibition couldexplain the neuroprotective effect of immuno- 3.4.2. Coenzymes Qsuppressive drugs in focal /cerebral ischemia [202]. Besides its antioxidant effects and its role in theThis idea was reinforced by the fact that a protecting regulation of electron transfer, a new property of theeffect against reperfusion injury was ascertained with coenzyme Q family was recently provided by Ber-the calcineurin inhibitor FK506 in heart and brain nardi’s group. They demonstrated that exogenous[203,204] while this drug did not inhibit PTP gene- coenzyme Q (ubiquinone 0) and decylubiquinone0

ration [205]. were very potent inhibitors of PTP opening induced21Thus, the existence of PTP in brain cells and, its by Ca overload whereas coenzyme Q (ubiquinone1

involvement in the neuroprotective properties of 5), which did not inhibit pore opening per se,CsA, which have been demonstrated in several counteracted the effects of coenzyme Q and de-0

models, is still a source of debate. cylubiquinone [210,211]. In addition, like CsA theseIts occurrence seems to be highly dependent from compounds inhibit PTP whatever the PTP inducer

the experimental in vitro conditions, from the brain used (phosphate, membrane depolarization, atrac-cell and region considered and from the ischemic tylate or oxidative stress). They concluded that amodel used in vivo [198,206]. At the present time specific quinone binding site modulate PTP opening.one must conclude that the cellular protective effect Whether this property takes part in the antiischemic


effect of coenzyme Q remains, to our knowledge, which are shown to have acute effects in ischaemicunexplored but these findings may open a new field models have effects in neurodegenerative diseases.of investigation to design a novel structural chemicalclass of pore inhibitors.

5. The particular case of the preservingsolutions for organ transplantation

3.4.3. Other pharmacological inhibitorsNumerous drugs were found to inhibit PTP in

Transplantation is a particular aspect of ischemiavitro [212]. Most of these drugs are amphiphilic

reperfusion injury with an uncommon kind of inflam-cations which are known to interact with biological

mation. Delayed graft function is clearly associatedmembranes and could change mitochondrial potential

with poor allograft function, and is caused by anwhich has also been proposed to explain the closure

interaction of ischemic and immunological factors.of the pore [207]. Indeed cationic compounds such

In addition, delayed graft function complicates post-as sphingosine [207], spermine [213] and divalent

operative patient management. Many factors maycations [214], which are believed to render the

contribute to the development of ischemia injury.membrane potential more positive, inhibit pore open-

The most important are the donor related factorsing. This hypothesis may be applied to trimetazidine

(hypotension and bread-death related phenomena),which is a divalent cation and could perhaps modify

cold ischemia (duration and method of storage),the surface potential. It is interesting to note that we

reperfusion injury, and the recipient factors. Pre-recently described the presence of specific binding

servation solutions have been designed to minimize3sites for [ H]trimetazidine on liver mitochondrialischemic damage during storage. Components are

membranes which may be involved in the regulationadded to decrease cell swelling, maintain calcium

of the mitochondrial permeability transition porehomeostasis, decrease free radical substrate forma-

[212,215].tion and provide high energy substrates [220].

Generally, these effect were observed at highThese goals are fulfilled by drugs which preserve

concentrations incompatible with their therapeuticand maintain mitochondrial functions, i.e. oxidative

concentrations. Few drugs escape this general rule. 21phosphorylation, Ca homeostasis and the limita-Amiodarone [216], trifluoperazine [217] and cin-

tion of ROS generation. Trimetazidine is a goodnarizine [218] act in the micromolar range and this

example of such a drug (see Section 3.1.1.1.). It haseffect can be expected to participate to their antiis-

been used to protect myocardium, liver, kidney andchemic effect.

small bowel from ischemia–reperfusion injury [221–224]. This drug was also efficient against coldischemia. Trimetazidine was shown to improve the

4. Metabolic diseases, ischaemia and stress: preservation of arrested rat hearts [225] and of piginteractions with mitochondria kidneys exposed to cold ischemia [226]. Interesting-

ly, we have recently demonstrated that the limitationGlutamate is produced via oxidative metabolism of ischemia reperfusion injury by trimetazidine was

via the Krebs cycle (Fig. 4) and GABA is also a also efficient against inflammatory cell infiltrationsubstrate for the Krebs cycle yielding up to 17% of [227]. This drug acts mainly at the renal medullaneuronal energy requirements in some instances. level which is extremely susceptible to injury inLactate is produced from astrocytes as a local energy reducing ischaemia–reperfusion injury [228].source from neurones. Thus ischaemia will markedly Ranolazine (see Section 3.1.1.2.) has also demon-change brain function in that the metabolism of the strated a beneficial effect in a porcine model of renalmain excitatory and inhibitory neurotransmitters will autotransplantation [229] but these authors havebe disrupted. Mitochondria are critical in neurode- probably renounced to use this drug in cold ischemiagenerative diseases [219]. Thus it will be interesting since, to our knowledge, any study had confirmedto see if the compounds reviewed in this chapter these results.


Fig. 4. Mitochondria, stress and ischemia. AMPA R, a-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid receptor; NMDA R, N-methyl-D-aspartate receptor; GAD, glutamic acid decarboxylase.

6. Conclusions regulate the cellular metabolism. They representpotential targets for drugs but the role of the organite

This brief review reveals that during the past 10 in the cell is so crucial that the drug effect must beyears numerous drugs have been shown to modulate specific and moderate. Such a drug is difficult tomitochondrial functions but none of them displays develop but the increasing number of works analyz-enough selectivity to assume the name of ‘mito- ing the interaction between drugs and mitochondriachondrial antiischemic drug’. Mitochondria contain a probably mean that a ‘mitochondrial drug’ exists inlot of enzymes, channels and exchangers which the near future.


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mitochondria as target for antiischemic drugs

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