department of neurosurgery, university of california san ... · department of neurosurgery,...

NEUROSURGICAL

FOCUS Neurosurg Focus 46 (3):E6, 2019

Spinal cord injury (SCI) remains a devastating prob-lem, with traumatic SCI affecting 12,400 individuals annually and 250,000 living survivors reported to

reside in the United States in July 2005.13 The prevalence of nontraumatic SCI is estimated to be 3–4 times greater than traumatic SCI.36 A variety of complications, includ-ing genitourinary and respiratory complications, often oc-cur after SCI with rehospitalization rates of up to 55% in the 1st year after SCI and around 37% for every year there-after for 20 years.8 Moreover, while 58.1% of patients are

employed before injury, only 12.1% remained employed 1 year after injury. As a manifestation of both indirect and direct cost, patients sustaining an SCI at age 25 years can expect a lifetime cost of $4.6 million for high tetraplegia and $2.3 million for paraplegia.13 There remains a need to improve recovery after SCI, considering its high incidence and these associated complications.

The pathophysiology involved in SCI includes multiple mechanisms such as the shearing of axons,45 followed by neural death due to ischemia,28 production of inflamma-

ABBREVIATIONS AIS = American Spinal Injury Association Impairment Scale; ALS = amyotrophic lateral sclerosis; SCI = spinal cord injury.SUBMITTED October 31, 2018. ACCEPTED January 2, 2019.INCLUDE WHEN CITING DOI: 10.3171/2019.1.FOCUS18596.

Efficacy of riluzole in the treatment of spinal cord injury: a systematic review of the literatureShanmukha Srinivas, BS, Arvin R. Wali, MD, MAS, and Martin H. Pham, MD

Department of Neurosurgery, University of California San Diego School of Medicine, San Diego, California

OBJECTIVE Riluzole is a glutamatergic modulator that has recently shown potential for neuroprotection after spinal cord injury (SCI). While the effects of riluzole are extensively documented in animal models of SCI, there remains het-erogeneity in findings. Moreover, there is a paucity of data on the pharmacology of riluzole and its effects in humans. For the present study, the authors systematically reviewed the literature to provide a comprehensive understanding of the effects of riluzole in SCI.METHODS The PubMed database was queried from 1996 to September 2018 to identify animal studies and clinical trials involving riluzole administration for SCI. Once articles were identified, they were processed for year of publication, study design, subject type, injury model, number of subjects in experimental and control groups, dose, timing/route of administration, and outcomes.RESULTS A total of 37 studies were included in this study. Three placebo-controlled clinical trials were included with a total of 73 patients with a mean age of 39.1 years (range 18–70 years). For the clinical trials included within this study, the American Spinal Injury Association Impairment Scale distributions for SCI were 42.6% grade A, 25% grade B, 26.6% grade C, and 6.2% grade D. Key findings from studies in humans included decreased nociception, improved motor func-tion, and attenuated spastic reflexes. Twenty-six animal studies (24 in vivo, 1 in vitro, and 1 including both in vivo and in vitro) were included. A total of 520 animals/in vitro specimens were exposed to riluzole and 515 animals/in vitro speci-mens underwent other treatment for comparison. The average dose of riluzole for intraperitoneal, in vivo studies was 6.5 mg/kg (range 1–10 mg/kg). Key findings from animal studies included behavioral improvement, histopathological tissue sparing, and modified electrophysiology after SCI. Eight studies examined the pharmacology of riluzole in SCI. Key findings from pharmacological studies included riluzole dose-dependent effects on glutamate uptake and its modified bioavailability after SCI in both animal and clinical models.CONCLUSIONS SCI has many negative sequelae requiring neuroprotective intervention. While still relatively new in its applications for SCI, both animal and human studies demonstrate riluzole to be a promising pharmacological intervention to attenuate the devastating effects of this condition.https://thejns.org/doi/abs/10.3171/2019.1.FOCUS18596KEYWORDS riluzole; spinal cord injury; neuroprotection; excitotoxicity; review

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Srinivas et al.

Neurosurg Focus Volume 46 • March 20192

tory molecules,12 and the rise of extracellular glutamate contributing to excitotoxicity.43 Current acute manage-ment strategies of SCI include surgical decompression,19 maintenance of arterial pressure with fluids and vasocon-strictors,52 and methylprednisolone, an antiinflammatory corticosteroid that inhibits transmigration of neutrophils and macrophages into the spinal cord, thereby reducing peroxidation of lipids in the cell membrane.3 However, there remains a need for greater neuroprotective agents to promote long-term recovery after SCI.

Riluzole, a glutamatergic modulator used primarily in amyotrophic lateral sclerosis (ALS),26 is currently be-ing evaluated for use in SCI. Riluzole activates guanosine triphosphate–binding signal transduction proteins (G-pro-teins), resulting in inhibition of neurotransmitter release.14 Riluzole also indirectly inhibits phospholipase A2 (PLA2), preventing release of arachidonic acid, and directly inhibits protein kinase C (PKC).42 Recent studies have suggested that riluzole is neuroprotective in neurodegenerative and traumatic injuries through its blockade of sodium chan-nel overactivation and modulation of glutamate uptake,4 as well as its stimulation of brain-derived neurotrophic factor expression.29 The use and effects of riluzole specifically in SCI, however, remain relatively new.

In this article, we aim to provide an overview of rilu-zole’s potential effectiveness in SCI and review current pharmacological, animal study, and clinical trial findings with this treatment.

MethodsA systematic review to analyze the use of riluzole in

SCI was performed through PubMed with articles dating from 1996 to September 2018 (Fig. 1). The search term was “riluzole Spinal Cord Injury.” This search yielded 99 results. Articles were included within this review if they presented primary human or animal data or investigated the pharmacology of riluzole in spinal cord injury. By this method, 37 experimental studies met the inclusion and ex-clusion criteria.

The extracted articles were then divided into 3 catego-ries: 1) animal studies describing therapeutic benefit, 2) clinical studies describing outcomes, and 3) pharmaco-logical studies. Two studies contributed findings to both pharmacology and therapeutic benefit in animals.39,58 Ani-mal studies were evaluated for study design (in vivo vs in vitro); animal type; injury model; number of animals included in experimental and control groups; dose; timing and route of administration; and outcomes measured by behavior, histopathology, and electrophysiology. Clinical trials were reviewed for study design, number of patients in experimental and control groups, SCI level, American Spinal Injury Association Impairment Scale (AIS) grade, average age, timing and route of administration, dosage, adverse events, and outcomes measured by sensory and motor functional tests. Pharmacological studies were eval-uated for study design, subject type, injury model, number of patients in experimental and control groups, timing and route of administration dosage, adverse effects and out-comes measured by electrophysiology, neurotransmitter uptake, receptor expression, and pharmacokinetics.

ResultsPharmacological Studies

Despite extensively published research on the phar-macology of riluzole, there are few studies reporting its effects on SCI. In this review, 8 studies on the pharmaco-logical effect of riluzole in SCI were included. Pharma-cological studies described the mechanisms of action and pharmacokinetics of riluzole in vivo, in vitro, and in hu-man studies. The major findings included decreased rilu-zole bioavailability in the spinal cord after SCI,10,15 with 1 study suggesting the opposite;58 blockage of sodium cur-rents with riluzole after SCI;25 and increase in glutamate uptake and expression,3,38,53 with 1 study suggesting no effect of riluzole on glutamate release after SCI.35 A full description of the pharmacology articles within this study can be found in Table 1.

Animal StudiesTwenty-six animal studies describing the therapeutic

effects of riluzole after SCI were included. There were 24 in vivo studies, 1 in vitro study, and 1 mixed study. A total of 520 animals/in vitro specimens were exposed to riluzole and 515 animals/in vitro specimens underwent other treatments for comparison. The average dose of rilu-zole used was 6.5 mg/kg in 7 in vivo studies in rats with predominantly intraperitoneal administration, with a few exceptions instead involving intrathecal and intracere-broventricular24 or intravenous administration33 and rab-bits.31–33,39 For behavioral studies, locomotion was evalu-ated with the rotarod, grid walk, open field, and pellet-reaching tasks; strength was evaluated with the inclined plane test; and sensory function was evaluated with the hind paw withdrawal test. A plethora of behavioral stud-ies demonstrated positive effects of riluzole on motor function including locomotion,21,27,34,38,48,58,57 strength,1,47,48 and stance and stride length.47,49 With regard to sensory function, behavioral studies have suggested that riluzole decreases nociception24 and spastic reflexes,30 which is both encouraging for reduction of neuropathic behaviors and concerning for decreased response to noxious stimuli. Histopathological experiments have shown that after SCI, riluzole increased rostrocaudal and epicenter tissue spar-ing with decreased lesion volume, increased axonal spar-ing, and increased serotonergic fibers.38,48,55 Other studies have shown an increase in glial cell and neuronal surviv-al,6,34,44,58 decrease in reactive oxygen species,49 increase in synaptophysin expression in the ventral horn,47 decrease in capillary fragmentation,50 decrease in pyknosis and hypoplasia of ventral motor neurons,49 decrease in lym-phocytes and granulocytes,7 increase in choline acetyl-choline transferase staining in motor neurons,21 decrease in lactate dehydrogenase,23 decrease in TUNEL staining apoptotic neurons,32,58,57 decrease in macrophages and microglia,58 and decrease in lipid peroxidation and water content.1 Electrophysiological experiments have suggested a decrease in muscle spasm,5 attenuation of altered reflex mechanisms,47 and increase in amplitude of somatosen-sory evoked potentials.58 Key findings within the animal data demonstrate spinal cord tissue sparing with cell sur-vival after SCI,1,6,33,31–34,38,39,41,44,46,48,55,57,58 reduced inflam-


Srinivas et al.

Neurosurg Focus Volume 46 • March 2019 3

matory mediators and sequelae,7,49 improved locomo-tion,1,7, 21,27,30,31–34,38,44,49,55 and decreased aberrant sensory responses.5,24 A full description of animal studies and the results from these investigations can be found in Table 2.

Human Clinical StudiesThree clinical studies were included in this systematic

review. The average age of the patients was 39.1 years (range 18–70 years). In total, the percentage of patients included by AIS grade was 42.6% grade A, 25% grade B, 26.6% grade C, and 6.2% grade D. Most patients in the clinical studies included were severely impaired at base-line. The major findings from clinical studies included decreased pain,37 increased motor functionality,22 and de-creased spastic reflexes54 after administration of riluzole for SCI. Specifically, with regard to motor function, Mesh-kini et al.37 and Grossman et al.22 demonstrated statisti-cally significant general motor improvement with riluzole at 6 and 3 months after acute SCI, respectively, while The-iss et al.54 showed strong correlation of riluzole use with lower-limb volitional strength for patients with chronic, incomplete SCI. Of the 3 clinical studies included, only Meshkini et al.37 evaluated reduction in pain after riluzole use, and only Theiss et al.54 evaluated attenuation of spas-tic reflexes. Clinical studies consistently demonstrated in-complete recovery after SCI despite the use of riluzole as manifested by low motor10,37 and sensory37 scores as well as debilitated voluntary contraction.54 All patients in clini-cal studies were administered 50 mg of riluzole enterally. However, while Meshkini et al.37 and Grossman et al.22 in-cluded a longitudinal dose of 50 mg BID (twice daily) for

8 and 4 weeks, respectively, Theiss et al.54 only included a one-time dose of 50 mg before testing. Overall, riluzole showed promising results with a decrease in neuropathic pain and severity of SCI,37 increase in motor function22 for cervical injury, and decrease in spasticity with preser-vation of normal voluntary movement.54 However, these benefits were not without risk for complications, as 14%–70% of patients in the Grossman study had elevated liver enzymes and bilirubin levels, implying potentially hepato-toxic effects of riluzole in humans.22 A full description of clinical studies included within this analysis can be found in Table 3.

DiscussionThis systematic review describes the potential use of

riluzole for efficacy after SCI in humans and animals in improving functional and neurological outcomes after SCI, including positive neuroprotective results.18 Primary and secondary damage in SCI is mediated primarily by excito-toxicity16 and thus riluzole, a prominent antiglutamatergic agent,56 has been a treatment of interest for SCI. Increased expression of glutamate transporters (EAAC1, GLST, and GLT-1) has been implicated in SCI with riluzole treatment increasing uptake activity of glutamate and attenuating any neuropathic pain sequelae from SCI.53 Moreover, riluzole blocks persistent inward sodium currents and fast sodium spikes, which are particularly important in chronic SCI.25 There is now a consensus that in neurodegenerative dis-orders, riluzole works predominantly through increasing glutamate uptake in astrocytes and presynaptic neurons,

FIG. 1. Ninety-nine clinical studies regarding the use of riluzole in spinal cord injury were initially identified. Twenty-seven articles were removed for inadequate access to the full article. Seventy-two papers were fully reviewed. After applying inclusion and exclu-sion criteria, 37 articles were selected for review and analysis.


Srinivas et al.


TABL

E 1.

Phar

mac

olog

y of r

iluzo

le in

SCI

Auth

ors

& Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

el Ex

perim

enta

l Grp

Contr

ol Gr

pDo

seTi

ming

Route

Adve

rse

Effec

tsM

ain F

inding

s

Dulin

et

al.,

2013

The d

ual c

yclo-

ox y g

enas

e/5-

lipox

ygen

ase i

nhibi

tor

licofe

lone a

ttenu

ates

p-gly

copr

otein-

medi-

ated d

rug r

esist

ance

in

the i

njure

d spin

al co

rd

In viv

o Ra

tM

oder

ate

contu

sion/

comp

ress

ion

injur

y at T

10

w/ In

finite

Ho

rizon

Spi-

nal Im

pacto

r De

vice

Grp 1

(n =

7): S

CI +

rilu-

zole;

grp 2

(n =

8): S

CI

+ rilu

zole

+ lic

ofelon

e (to

tal: 1

5)

Sham

+

riluzo

le (n

=

7)

8 mg/ kg

3 hrs

posti

n-jur

y & on

ce

daily

for 3

da

ys

IPTx

-ass

ociat

ed

morta

lity

of 30

% in

rilu

zole

grp

1) Pg

P im

muno

reac

tivity

&

gene

tic ex

pres

-sio

n ↑ in

epice

nter &

dis

tant

rostr

ocau

dal

area

s pos

t-SCI

; 2)

riluzo

le bio

avail

abilit

y (sp

inal c

ord/p

lasma

ra

tio) is

sign

ifican

tly

lower

post-

SCI; 3

) kn

ockin

g out

PgP

gene

ticall

y & at

tenu-

ating

PgP

expr

essio

n w/

licofe

lone c

ause

s ↑

deliv

ery o

f rilu

zole

to sp

inal c

ord

Wu e

t al.,

2013

Delay

ed po

st-inj

ury

admi

nistra

tion o

f rilu

zole

is ne

urop

ro-

tectiv

e in a

prec

lini-

cal ro

dent

mode

l of

cerv

ical s

pinal

cord

inj

ury

In viv

oRa

tC7

–T1 s

pinal

cord

com

-pr

essio

n ex

tradu

rally

w/

mod

ified

aneu

rysm

cli

p

Grp 1

(n =

6): 8

mg/kg

1 hr

po

stinju

ry, th

en 8

mg/

kg B

ID fo

r 7 da

ys; g

rp

2 (n =

10): 6

mg/

kg 1

hr

posti

njury,

then

6 mg

/kg

BID

for 7

days

; grp

3 (

n = 6)

: 4 m

g/kg

1 hr

po

stinju

ry, th

en 4

mg/kg

BI

D for

7 da

ys; g

rp 4

(n = 1

2) (p1

): 8 m

g/kg

at 1

hr po

stinju

ry, th

en 6

mg/

kg B

ID fo

r 7 da

ys; g

rp

5 (n =

12) (

p3): 8

mg/

kg

at 3 h

rs po

stinju

ry, th

en

6 mg/

kg B

ID fo

r 7 da

ys

(total

: 46)

Grp

6 (n

=

12):

no

injur

y +

vehic

le

8, 6,

4 mg

/kg

1 or 3

hrs

posti

njury

&

BID

for 7

da

ys

IPNA

Riluz

ole is

subs

tanti

ally

highe

r in sp

inal c

ord

than

plas

ma &

half-

life ↑

post-

SCI

Chow

et

al.,

2012

Phar

maco

logy o

f rilu

-zo

le in

acute

spina

l co

rd in

jury

Phas

e 1

clinic

al tri

al

Huma

nHu

man

Grp 1

(n =

36)

: rilu

zole

Grp 2

(n

= 36

): co

ntrol

50 m

gBI

DPO

&

naso

-ga

stric

14–7

0% ha

d ele

vated

liv-

er en

zyme

s &

biliru

bin

levels

Max

conc

entra

tion &

sy

stemi

c exp

osur

e of

riluzo

le ar

e low

er in

SC

I pts

than

in A

LS

pts on

same

dose

; rilu

zole

has h

igher

cle

aran

ce &

larg

er

vol o

f dist

ribut

ion

in SC

I

CONT

INUE

D ON

PAG

E 5

»


Srinivas et al.


TABL

E 1.

Phar

mac

olog

y of r

iluzo

le in

SCI

Auth

ors

& Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

el Ex

perim

enta

l Grp

Contr

ol Gr

pDo

seTi

ming

Route

Adve

rse

Effec

tsM

ain F

inding

s

Harv

ey

et al.

, 20

06

Pers

isten

t sod

ium cu

r-re

nts an

d rep

etitiv

e fir

ing in

moto

neur

ons

of th

e sac

roca

udal

spina

l cor

d of a

dult

rats

In vit

ro &

in

vivo

Rat

Acute

SCI

: tra

nsec

tion

at S2

in vi

vo;

chro

nic S

CI:

trans

ectio

n at

S2 at

age

40–5

5 day

s

Grp 1

(n =

41):

acute

SCI

in

vivo;

grp 2

(n =

24):

chro

nic S

CI in

vivo

; gr

p 3 (n

= 9)

: in vi

tro

(tota

l: 74)

20 μ

MPo

st-tis

sue

harv

estin

gIn

vitro

NA

Riluz

ole bl

ocks

pers

is-ten

t inwa

rd cu

rrents

of

sodiu

m in

in vit

ro

sacr

ocau

dal s

pinal

cord

segm

ents

McA

doo

et al.

, 20

05

The e

ffect

of glu

tama

te re

cepto

r bloc

kers

on

gluta

mate

relea

se

follo

wing

spina

l co

rd in

jury.

Lack

of

evide

nce f

or an

on

going

feed

back

ca

scad

e of d

amag

e →

glut

amate

relea

se

→ da

mage

→ gl

uta-

mate

relea

se →

etc.

In viv

oRa

tW

eight

drop

on

MAS

CIS

impa

ctor

(T10

)

Grp 1

(n =

6): r

iluzo

leGr

p 2 (n

= 6)

: co

ntrol

2.0 m

MCo

ntinu

ous

from

prein

-jur

y to 4

hrs

posti

njury

Micr

odi-

alysis

fib

er

NARi

luzole

does

not a

ffect

gluta

mate

relea

se

post-

SCI

Sung

et

al.,

2003

Alter

ed ex

pres

sion

and u

ptak

e acti

vity

of sp

inal g

lutam

ate

trans

porte

rs af

ter

nerv

e inju

ry co

ntrib-

ute to

the p

athog

en-

esis

of ne

urop

athic

pain

in ra

ts

In viv

o Ra

tCh

ronic

co

nstri

ction

ne

rve i

njury

Grp 1

(n =

6): C

CI +

1 mg

/kg

riluz

ole pr

e-Tx

; grp

2 (

n = 6)

: CCI

+ 4

mg/

kg ri

luzole

pre-

Tx; g

rp 3

(n =

6): C

CI +

1 mg

/kg

post-

Tx; g

rp 4

(n =

6):

CCI +

4 mg

/kg po

st-Tx

(to

tal: 2

4)

Grp 5

(n =

6)

: CCI

+

vehic

le;

grp 6

(n =

6)

: sha

m +

4 mg/

kg po

st-Tx

(to

tal: 1

2)

1 or 4

mg

/kg

Pre-

Tx (g

rps 1

&

2): st

arts

imme

diatel

y po

stinju

ry;

post-

Tx

(grp

s 3 &

4):

star

ts 5

DPI; B

ID fo

r 4 d

ays f

or

both

grps

IPNA

SCI in

duce

s sign

ifican

t ex

pres

sion o

f spin

al glu

tama

te tra

nspo

rt-er

s (EA

AC1,

GLST

, GL

T-1) in

ipsil

esion

al sp

inal c

ord d

orsa

l ho

rn; r

iluzo

le sig

-nifi

cantl

y ↑ gl

utam

ate

upta

ke in

ipsil

esion

al sp

inal c

ord d

orsa

l ho

rn; r

iluzo

le ad

min-

ister

ed im

media

tely

posti

njury

or 5

DPI

atten

uates

neur

o-pa

thic

beha

viors

inc

luding

ther

mal

hype

ralge

sia &

me-

chan

ical a

llody

nia

CONT

INUE

D ON

PAG

E 6

»

» CON

TINU

ED F

ROM

PAGE

4


Srinivas et al.


TABL

E 1.

Phar

mac

olog

y of r

iluzo

le in

SCI

Auth

ors

& Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

el Ex

perim

enta

l Grp

Contr

ol Gr

pDo

seTi

ming

Route

Adve

rse

Effec

tsM

ain F

inding

s

Azbil

l et

al.,

2000

Riluz

ole in

crea

ses h

igh-

affin

ity gl

utam

ate

upta

ke in

rat s

pinal

cord

syna

ptoso

mes

In vit

ro &

in

vivo

Rat

None

Gr

p 1 (n

= 6)

: rilu

zole

Grp 2

(n =

6):

salin

e8 m

g/ kg2×

w/ 2

hrs

btwn

inj

ectio

n (e

utha

nasia

2 h

rs af

ter

last in

jec-

tion)

IPNA

Riluz

ole ↑

glut

amate

up

take

in sp

inal c

ord

syna

ptoso

mes a

t 1 &

0.1

μM

in vit

ro bu

t not

at hig

her d

oses

; 0.1

μM ri

luzole

caus

es

21%

↓ in

Km

& 31

% ↑

in

Vmax

of gl

utam

ate

Mu e

t al.,

2000

39Ri

luzole

impr

oves

me

asur

es of

oxida

-tiv

e stre

ss fo

llowi

ng

traum

atic s

pinal

cord

inj

ury

In viv

oRa

bbit

Contu

sion i

njury

(im

pacto

r rod

at

T10)

Grp 1

(n =

9): r

iluzo

le;

grp 2

(n =

9): r

iluzo

le +

methy

lpred

nisolo

ne

(tota

l: 18)

Grp 3

(n =

9):

vehic

le;

grp 4

(n =

9)

: meth

yl-pr

ednis

o-lon

e (tot

al:

18)

8 mg/ kg

15 m

ins &

2 hr

s pos

tin-

jury

IPNA

Riluz

ole ↑

glut

amate

&

gluco

se up

take

po

st-SC

I

BID

= tw

ice da

ily; C

CI =

chro

nic co

nstri

ction

injur

y; DP

I = da

ys p

ostin

jury;

grp =

grou

p; IP

= in

trape

riton

eal; M

ASCI

S =

Mult

icente

r Anim

al Sp

inal C

ord I

njury

Stu

dy; m

ax =

max

imum

; NA

= no

t ava

ilable

; PO

= by

mou

th; pt

s =

patie

nts;

p1 =

rats

treate

d with

riluz

ole at

1 ho

ur p

ostin

jury;

p3 =

rats

treate

d with

riluz

ole at

3 ho

urs p

ostin

jury;

Tx =

trea

tmen

t; ↑ =

incr

ease

/incr

ease

s/inc

reas

ed/in

crea

sing;

↓ =

decr

ease

/decr

ease

s/dec

reas

ed/de

crea

s-ing

.Ei

ght s

tudie

s with

6 in

vivo e

xper

imen

ts, 3

in vit

ro ex

perim

ents,

and 1

huma

n stu

dy.

» CON

TINU

ED F

ROM

PAGE

5


Srinivas et al.


TABL

E 2.

Impa

ct o

f rilu

zole

on S

CI in

in vi

tro an

d in

vivo

anim

al ex

perim

ents

Auth

ors &

Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

el Ex

perim

enta

l Grp

Contr

ol Gr

pDo

seTi

ming

Route

Main

Find

ings

Cagla

r et

al.,

2018

Effec

t of r

iluzo

le on

spina

l cor

d re

gene

ratio

n wi

th he

mise

ction

me

thod

befo

re

injur

y

In viv

oRa

tHe

mise

ction

af

ter T

7–9

lamnie

ctomy

Grps

1–6 &

8 (n

= 28

): rilu

zole

Grp 7

(n =

4):

vehic

le 6 m

g/kg

Grps

1 &

6: 12

hrs

pre-

SCI &

BID

po

st-SC

I unti

l 7

DPI; g

rps 2

& 5:

1 hr

pre-

SCI &

BID

po

st-SC

I unti

l 7

DPI; g

rps 3

& 4:

BI

D po

st-SC

I unti

l 7 D

PI; g

rp 8:

BID

fo

r 5 da

ys pr

e-SC

I bu

t not

post-

SCI

IP

Histo

path

ology

: ear

ly rilu

zole

Tx

caus

es lo

wer h

istop

atholo

gical

spina

l cor

d tiss

ue da

mage

&

↑ no

. of s

urviv

ing gl

ial ce

lls &

ne

uron

s

Shim

izu

et al.

, 20

18

Prop

hylac

tic ri

luzole

at

tenua

tes

oxida

tive s

tress

da

mage

in sp

inal

cord

distr

actio

n

In viv

oRa

tBi

direc

tiona

l spi-

nal d

istra

ctor

devic

e

Grp 1

(n =

54):

riluz

oleGr

p 2 (n

= 5

4):

vehic

le8 m

g/kg

ini

tial

dose

, th

en

6 mg/

kg

BID

IPHi

stopa

tholo

gy: r

iluzo

le Tx

↓ re

ac-

tive o

xyge

n spe

cies f

orma

tion

& at

tenua

tes py

knos

is &

hypo

-pla

sia of

ventr

al mo

tor ne

uron

s po

st-SC

IBe

havio

r: rilu

zole

Tx m

ainta

ins

norm

al ga

it pos

t-SCI

as m

ea-

sure

d by ↑

stan

ce du

ratio

n & ↓

str

ide le

ngth

Mar

tins

et al.

, 20

18

Asso

ciatio

n of

riluzo

le an

d da

ntrole

ne im

-pr

oves

sign

ifican

t re

cove

ry af

ter

acute

spina

l cor

d inj

ury i

n rats

In viv

oRa

tEx

tradu

ral

comp

ress

ion

of do

rsal

sur-

face o

f spin

al co

rd us

ing

weigh

t

Grp 1

(n =

5):

lamine

ctomy

+

SCI +

riluz

ole +

pla

cebo

(15 m

ins &

1 h

r pos

tlami

nec-

tomy);

grp 2

(n =

6):

lamine

ctomy

+ S

CI

+ rilu

zole

+ da

n-tro

lene (

15 m

ins/1

hr po

stlam

inec-

tomy)

(tota

l: 11)

Grp 3

(n =

6): la

mi-

necto

my +

pla-

cebo

; grp

4 (n

=

6): la

mine

ctomy

+

SCI; g

rp 5

(n =

6)

: lami

necto

my

+ SC

I + pl

aceb

o +

dantr

olene

(15

mins

/1 hr

po

stlam

inec-

tomy)

(tota

l: 18)

4 mg/

kg15

mins

& 1

hr

postl

amine

ctomy

IP

Im

muno

histo

chem

istry

: whe

n co

mbine

d w/ d

antro

lene,

riluzo

le sig

nifica

ntly ↑

neur

on

surv

ival in

epice

nter o

f injur

y &

caud

al re

gions

as w

ellBe

havio

r: wh

en co

mbine

d w/

dantr

olene

, rilu

zole

impr

oves

hin

dlimb

perfo

rman

ce on

BBB

sc

ale; r

iluzo

le alo

ne do

es no

t im

prov

e hind

limb p

erfo

rman

ce

Can e

t al.,

2017

Comb

ined a

nd

indivi

dual

use

of pa

ncas

pase

inh

ibitor

Q-V

D-OP

h and

NM

DA

rece

ptor a

ntag

o-nis

t rilu

zole

in ex

perim

enta

l sp

inal c

ord i

njury

In viv

oRa

tCl

ip co

mpre

s-sio

n via

T7–9

lam

inecto

-mi

es

Grp 1

(n =

9): S

CI +

rilu

zole

only;

grp 2

(n

= 9)

: SCI

+ bo

th rilu

zole

& Q-

VD-

OPh (

total:

18)

Grp 3

(n =

9): S

CI

only;

grp 4

(n =

9)

: SCI

+ ve

hicle;

gr

p 5 (n

= 9)

SCI

+

Q-VD

-OPh

(p

anca

spas

e inh

ibitor

) only

(to

tal: 2

7)

5 mg/

kg1 h

r pos

tinjur

yIP

Hi

stopa

tholo

gy: r

iluzo

le Tx

sign

ifi-ca

ntly ↓

lymp

hocy

te co

unt &

po

lymor

phon

uclea

r leuk

ocyte

s/gr

anulo

cytes

post-

SCI; r

iluzo

le Tx

does

not s

ignific

antly

at-

tenua

te no

. of a

popto

tic ce

lls

post-

SCI

Beha

vior:

riluzo

le sig

nifica

ntly

impr

oves

clini

cal m

otor s

core

&

inclin

ed pl

ane s

core

post-

SCI

CONT

INUE

D ON

PAG

E 8

»


Srinivas et al.


TABL

E 2.

Impa

ct o

f rilu

zole

on S

CI in

in vi

tro an

d in

vivo

anim

al ex

perim

ents

Auth

ors &

Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

el Ex

perim

enta

l Grp

Contr

ol Gr

pDo

seTi

ming

Route

Main

Find

ings

Glov

iczki

et al.

, 20

17

Delay

ed sp

inal

cord

-bra

chial

ple

xus r

econ

-ne

ction

after

C7

ventr

al ro

ot av

ul-sio

n: th

e effe

ct of

reinn

erva

ting

moton

euro

ns

resc

ued b

y rilu

-zo

le tre

atmen

t

In viv

oRa

tC7

ventr

al ro

ot av

ulsion

+ C

7 au

tolog

ous

nerv

e gra

ft

Grp 1

(n =

5): a

vulsi

on

+ im

media

te re

con-

necti

on +

riluz

ole;

grp 2

(n =

5): a

vul-

sion +

1-wk

delay

to

reco

nnec

tion +

rilu

zole;

grp 3

(n =

5)

: avu

lsion

+ 3

-wk

delay

to re

conn

ec-

tion +

riluz

ole (t

otal:

15

)

Grp 4

(n =

5): a

vul-

sion +

imme

diate

reco

nnec

tion;

grp 5

(n =

5):

avuls

ion +

1-wk

de

lay to

reco

n-ne

ction

; grp

6 (n

= 5)

: avu

lsion

+

3-wk

delay

to

reco

nnec

tion

(tota

l: 15)

5 mg/

kg

Daily

for 1

st wk

&

ever

y 2nd

day f

or

2nd w

k

IPHi

stopa

tholo

gy: r

iluzo

le Tx

sign

ifi-ca

ntly i

mpro

ves m

otor n

euro

n su

rviva

l inde

pend

ent o

f timi

ng

of re

conn

ectio

n pro

cedu

re re

la-tiv

e to i

njury

Beha

vior:

riluzo

le sig

nifica

ntly

impr

oves

pelle

t rea

ching

&

dors

iflexio

n afte

r rec

onne

ction

af

ter ve

ntral

root

avuls

ion

Broc

ard

et al.

, 20

16

Clea

vage

of N

a+ ch

anne

ls by

ca

lpain

incre

ases

pe

rsist

ent N

a+ cu

rrent

and p

ro-

motes

spas

ticity

af

ter sp

inal c

ord

injur

y

In viv

oRa

tSp

inal c

ord

trans

ectio

n at

T9

Grp 1

(n =

8): 8

mg/

kg

once

; grp

2 (n

= 8)

: 4 m

g/kg

BID

for 2

wk

s; gr

p 3 (n

= 7)

: 1 m

g/kg

BID

for 2

wk

s (tot

al: 23

)

NA8 ,

4, &

1 m

g/kg

8 mg/

kg on

ce, 4

mg/

kg B

ID fo

r 2 w

ks,

or 1

mg/kg

BID

for

2 wks

IPEl

ectro

phys

iolog

y: as

mea

sure

d by

EM

G, ri

luzole

Tx at

mod

erate

do

se (8

or 4

mg/kg

) sign

ifican

tly

↓ mu

scle

spas

m &

augm

ents

musc

le sp

asm

redu

ction

whe

n vo

ltage

-gate

d sod

ium ch

anne

ls ar

e spa

red p

ost-S

CI; r

iluzo

le do

es no

t atte

nuate

mon

osyn

-ap

tic re

flexe

s ass

ociat

ed w

/ glu

tama

tergic

curre

ntsVa

scon

-ce

los

et al.

, 20

16

Comb

ining

ne

urop

rotec

tive

agen

ts: ef

fect

of rilu

zole

and

magn

esium

in

a rat

mode

l of

thor

acic

spina

l co

rd in

jury

In viv

oRa

tTh

orac

ic sp

inal c

ord

contu

sion w

/ we

ight d

rop

Grp 1

(n =

4): r

iluzo

le;

grp 2

(n =

5):

riluzo

le +

MgC

l (to

tal: 9

)

Grp 3

(n =

5):

salin

e; gr

p 4 (n

=

5): M

gCl (t

otal:

10

)

2.50

mg/

kg1 h

r pos

tinjur

yIP

Histo

path

ology

: rilu

zole

↓ les

ion

vol, ↑

axo

nal p

rese

rvati

on, &

↑

gluta

mater

gic &

sero

toner

gic

fiber

spar

ing ca

udal

but n

ot ro

stral

to ep

icente

r of in

jury;

riluzo

le do

es no

t sign

ifican

tly ↑

mo

tor ne

uron

surv

ival

Beha

vior:

riluzo

le sig

nifica

ntly

impr

oves

loco

motor

scor

e as

mea

sure

d on B

BB sc

ale;

riluzo

le sig

nifica

ntly ↑

dista

nce

trave

led in

activ

ity bo

x

CONT

INUE

D ON

PAG

E 9

»

» CON

TINU

ED F

ROM

PAGE

7


Srinivas et al.


TABL

E 2.

Impa

ct o

f rilu

zole

on S

CI in

in vi

tro an

d in

vivo

anim

al ex

perim

ents

Auth

ors &

Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

el Ex

perim

enta

l Grp

Contr

ol Gr

pDo

seTi

ming

Route

Main

Find

ings

Satku

nen-

drar

a-jah

et

al.,

2016

Riluz

ole pr

omote

s mo

tor an

d res

pi-ra

tory r

ecov

ery

asso

ciated

with

en

hanc

ed ne

uro-

nal s

urviv

al an

d fu

nctio

n foll

owing

hig

h cer

vical

spina

l hem

isec-

tion

In viv

oRa

tCo

mplet

e lt

hemi

secti

on

from

midli

ne

below

C2

dors

al ro

ot

Grp 1

(n =

18):

riluzo

leGr

p 2 (n

= 17

): ve

hicle

8 mg/

kg1 h

r pos

tinjur

y, th

en

BID

for 7

days

IPHi

stopa

tholo

gy: r

iluzo

le Tx

↑ sy

n-ap

tophis

in ex

pres

sion i

n cau

dal

cerv

ical v

entra

l hor

n; rilu

zole

Tx at

tenua

tes lo

ss of

NR2

A su

bunit

of N

MDA

rece

ptor &

Gl

uR1 s

ubun

it of A

MPA

rece

p-tor

; rilu

zole

atten

uates

moto

r ne

uron

loss

as m

easu

red b

y Ch

AT po

sitivi

ty on

ipsil

esion

al &

contr

alesio

nal s

ides o

f injur

yEl

ectro

phys

iolog

y: rilu

zole

Tx

atten

uates

injur

y-me

diated

alt

erati

on in

Hma

x/Mm

ax ra

tioBe

havio

r: rilu

zole

Tx im

prov

es

ipsila

t fore

limb g

rip st

reng

th as

early

as 3

DPI &

contr

alat

fore

limb g

rip st

reng

th as

early

as

19 D

PI; r

iluzo

le Tx

↑ st

ride

lengt

h, sw

ing sp

eed,

& fo

repa

w wi

dth o

n cat

walk

test f

rom

2 to

6 wks

posti

njury

; rilu

zole

Tx ↑

pe

ak am

plitu

de of

insp

irator

y bu

rsts

of ips

ilat d

iaphr

agm

2 wk

s pos

tinjur

yHa

chem

et

al.,

2015

Evalu

ation

of th

e ef

fects

of rilu

zole

on ad

ult sp

inal

cord

-der

ived

neur

al ste

m/pr

o-ge

nitor

cells

in

vitro

and i

n vivo

In viv

o +

in vit

roRa

tRo

dent

clip

comp

ress

ion

+ inj

ectio

n of

neur

al pr

o-ge

nitor

cells

in

prox

imal

rostr

al &

cau-

dal re

gions

to

injur

y ep

icente

r

Grp 1

(n =

4): r

iluzo

leGr

p 2 (n

= 4)

: ve

hicle

8 mg/

kg

Imme

diatel

y pos

t-tra

nspla

nt, 6

mg/

kg B

ID fo

r 3 da

ys,

then

once

daily

fo

r 10 d

ays

IP

Histo

path

ology

In vit

ro: e

xpos

ure t

o high

dose

s of

riluzo

le ↓

neur

al pr

ogen

itor

stem

cell s

urviv

al &

memb

rane

int

egrit

y; rilu

zole

does

not a

ffect

no. o

f livin

g or p

rolife

ratin

g ne

ural

prog

enito

r stem

cells

af

ter gl

utam

ate ex

posu

re.

In viv

o: rilu

zole

does

not a

ffect

surv

ival o

r phe

notyp

e of c

ells i

n ne

ural

prog

enito

r stem

cell g

raft

CONT

INUE

D ON

PAG

E 10

»

» CON

TINU

ED F

ROM

PAGE

8


Srinivas et al.


TABL

E 2.

Impa

ct o

f rilu

zole

on S

CI in

in vi

tro an

d in

vivo

anim

al ex

perim

ents

Auth

ors &

Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

el Ex

perim

enta

l Grp

Contr

ol Gr

pDo

seTi

ming

Route

Main

Find

ings

Hosie

r et

al.,

2015

A dir

ect c

ompa

rison

of

thre

e clin

ically

re

levan

t trea

t-me

nts in

a ra

t mo

del o

f cer

vical

spina

l cor

d inju

ry

In viv

o Ra

t Lo

wer c

ervic

al he

mico

rd

contu

sion

at C7

Grp 1

(n =

10):

riluzo

leGr

p 1 (n

= 10

): gli

benc

lamide

; gr

p 2 (n

= 10

): hy

poth

ermi

a; gr

p 3 (n

= 10

): ve

hicle

(tota

l: 30)

5 mg/

kg

BID

for 7

days

IP

Be

havio

r: rilu

zole

signifi

cantl

y im

prov

es lo

como

tor sc

ore o

n m

BBB

scale

3 wk

s pos

tinjur

y &

acce

lerati

ng ro

taro

d 5 w

ks

posti

njury

Wu e

t al.,

2014

Riluz

ole im

prov

es

outco

me fo

llow-

ing is

chem

ia-re

perfu

sion i

njury

to

the s

pinal

cord

by

prev

entin

g de-

layed

para

plegia

In viv

o Ra

tHi

gh th

orac

ic ao

rtic b

alloo

n oc

clusio

n

Grp 1

(n =

7): r

iluzo

leGr

p 2 (n

= 7)

: ve

hicle

8 mg/

kg

4 hrs

posti

njury

IPHi

stopa

tholo

gy: r

iluzo

le Tx

↑ ne

u-ro

n sur

vival

& ↓

no. o

f rea

ctive

as

trocy

tes in

lami

nae 7

& 9

but

not 2

; rilu

zole

Tx ↓

mac

ro-

phag

es &

micr

oglia

in la

mina

e 7,

8, &

9; rilu

zole

Tx at

tenua

tes

ische

mia-

relat

ed ap

optos

is as

me

asur

ed by

TUN

EL st

aining

W

u et a

l., 20

13De

layed

post-

injur

y ad

minis

tratio

n of

riluzo

le is

neur

opro

tectiv

e in

a pre

clinic

al ro

dent

mode

l of

cerv

ical s

pinal

cord

injur

y

In viv

oRa

tC7

–T1

extra

dura

l sp

inal c

ord

comp

ress

ion

for 1

min

w/

modifi

ed an

-eu

rysm

clip

Grp 1

(n =

6): 8

mg/

kg 1

hr po

stinju

ry,

then

8 mg

/kg B

ID

for 7

days

; grp

2 (n

= 10

): 6 m

g/kg

1 hr

posti

njury,

th

en 6

mg/kg

BID

fo

r 7 da

ys; g

rp 3

(n =

6): 4

mg/

kg 1

hr po

stinju

ry, th

en

4 mg/

kg B

ID fo

r 7

days

; grp

4 (p

1) (n

=

12):

8 mg/

kg at

1 hr

posti

njury,

then

6 m

g/kg

BID

for 7

da

ys; g

rp 5

(p3)

(n

= 12

): 8 m

g/kg

at 3

hrs p

ostin

jury,

then

6 m

g/kg

BID

for 7

da

ys (t

otal:

46)

Grp 6

(n =

12):

no

injur

y + ve

hicle

8, 6,

4 mg

/kg

1 or 3

hrs p

ostin

jury,

then

BID

for 7

da

ys

IP

Histo

path

ology

: ear

ly rilu

zole

Tx ↑

tis

sue s

parin

g cau

dal to

injur

y ep

icente

r & cy

toske

letal

integ

-rit

y of a

xons

whil

e ↓ ap

optos

is;

delay

ed ri

luzole

Tx do

es no

t sig

nifica

ntly r

educ

e apo

ptosis

; bo

th ea

rly &

delay

ed ri

luzole

Tx

impr

ove a

xona

l con

necti

ons &

re

duce

infla

mmati

on

CONT

INUE

D ON

PAG

E 11

»

» CON

TINU

ED F

ROM

PAGE

9


Srinivas et al.


TABL

E 2.

Impa

ct o

f rilu

zole

on S

CI in

in vi

tro an

d in

vivo

anim

al ex

perim

ents

Auth

ors &

Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

el Ex

perim

enta

l Grp

Contr

ol Gr

pDo

seTi

ming

Route

Main

Find

ings

Sáma

no

et al.

, 20

12

A stu

dy of

the p

o-ten

tial n

euro

pro-

tectiv

e effe

ct of

riluzo

le on

loco

-mo

tor ne

twor

ks

of th

e neo

nata

l ra

t spin

al co

rd in

vit

ro da

mage

d by

excit

otoxic

ity

In vit

roRa

tTr

ansie

nt ka

inate

(glut

amate

ag

onist

) at

0.05–

0.1 m

M to

prod

uce

excit

otoxic

ity

Grp 1

(n =

3): r

iluzo

le alo

ne fo

r 3 hr

s in

vitro

postk

ainate

wa

shou

t; grp

2 (n

=

3): r

iluzo

le alo

ne

for 2

4 hrs

in vi

tro

postk

ainate

was

h ou

t (tot

al: 6)

Grp 3

(n =

6):

sham

; grp

4 (n

=

3): 0

.05 m

M ka

inate

alone

(1

hr);

grp 5

(n =

6):

0.01 m

M ka

inate

alone

(1 hr

) (to

tal: 1

5)

5 μM

3 or 2

4 hrs

posti

njury

In vit

roHi

stopa

tholo

gy: c

ontin

uous

but n

ot sh

ort d

urati

on of

riluz

ole at

tenu-

ates p

ykno

sis in

dors

al, ce

ntral,

&

ventr

al ho

rns o

f spin

al co

rd;

conti

nuou

s dur

ation

of ri

luzole

↑

dors

al &

centr

al ne

uron

sur-

vival

w/ no

sign

ifican

t effe

ct on

ve

ntral

neur

on su

rviva

l; sho

rt du

ratio

n of r

iluzo

le ha

d opp

osite

ef

fect

Elec

troph

ysiol

ogy:

riluzo

le do

es

not s

ignific

antly

impr

ove p

eak

ampli

tude

of po

lysyn

aptic

re

spon

se to

dors

al ro

ot sti

mula-

tion o

r refl

ex ar

eaSi

mard

et

al.,

2012

Comp

arati

ve ef

fects

of gli

benc

lamide

an

d rilu

zole

in a r

at mo

del o

f se

vere

cerv

ical

spina

l cor

d inju

ry

In viv

o Ra

tUn

ilat c

ervic

al im

pacto

r on

dura

mate

r ne

ar lt

C8

nerv

e roo

t

Grp 1

(n =

3): r

iluzo

le;

grp 2

(n =

13):

riluzo

le (to

tal: 1

6)

Grp 3

(n =

3):

vehic

le; gr

p 4 (n

=

13):

glibe

n-cla

mide

; grp

5 (n

= 15

): ve

hicle

(tota

l: 31)

2.5 m

g/kg

Grp 1

: onc

e pos

tin-

jury;

grp 2

: 3 hr

s po

stinju

ry, th

en

BID

for 7

days

Grp 1

: IP;

gr

p 2:

os-

motic

pu

mp

injur

y

Histo

path

ology

: rilu

zole

Tx ↓

capil

-lar

y fra

gmen

tatio

n in p

enum

bral

micr

oves

sels

& ↑

NeuN

+ ne

uron

s in v

entra

l gra

y mat

ter

contr

alat to

injur

y site

; com

-pa

red w

/ glib

encla

mide

, rilu

zole

Tx ha

d sign

ifican

tly la

rger

lesio

n vo

l 6 w

ks po

st-SC

IBe

havio

r: co

mpar

ed w

/ glib

en-

clami

de, r

iluzo

le-tre

ated r

ats

had s

ignific

antly

wor

se gr

ip str

engt

h, pe

rform

ance

on

rota

rod,

& low

er m

BBB

scor

es

Hama

&

Sage

n, 20

11

Antin

ocice

ptive

ef

fect o

f rilu

zole

in ra

ts wi

th ne

u-ro

path

ic sp

inal

cord

injur

y pain

In viv

oRa

tCo

mpre

ssive

inj

ury t

o mi

dtho

-ra

cic (T

6/T7

) sp

inal c

ord w

/ mi

crov

ascu

lar

clamp

Grp 1

(n =

18):

ICV

deliv

ery p

ost-S

CI;

grp 2

(n =

18):

IT

deliv

ery p

ost-S

CI;

grp 3

(n =

11):

8 mg

/kg IP

(tot

al: 47

)

Grp 4

(n =

10):

ICV

vehic

le; gr

p 5 (n

=

12):

IT ve

hicle;

gr

p 6 (n

= 11

): IP

ve

hicle

(tota

l: 33)

IT/IC

V: 5

μl; IP

: 8 m

g/kg

4 wks

posti

njury

IT,

ICV,

&

IPBe

havio

r: IP

riluz

ole Tx

↓ no

ci-ce

ption

in he

althy

contr

ols &

ex

perim

enta

l anim

als un

derg

o-ing

SCI

; ICV

but n

ot IT

riluz

ole

↓ no

cicep

tion p

ost-S

CI

CONT

INUE

D ON

PAG

E 12

»

» CON

TINU

ED F

ROM

PAGE

10


Srinivas et al.


TABL

E 2.

Impa

ct o

f rilu

zole

on S

CI in

in vi

tro an

d in

vivo

anim

al ex

perim

ents

Auth

ors &

Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

el Ex

perim

enta

l Grp

Contr

ol Gr

pDo

seTi

ming

Route

Main

Find

ings

Pinté

r et

al.,

2010

Incr

ease

d sur

vival

and r

einne

rva-

tion o

f cer

vical

moton

euro

ns

by ri

luzole

after

av

ulsion

of th

e C7

ventr

al ro

ot

In viv

oRa

tC7

ventr

al ro

ot av

ulsion

+

reim

plant

a-tio

n

Grp 1

(n =

5): v

entra

l ro

ot av

ulsion

+

reim

plant

ation

+

riluzo

le; gr

p 2 (n

=

5): v

entra

l root

avuls

ion +

riluz

ole

(tota

l: 10)

Grp 3

(n =

5):

ventr

al ro

ot av

ulsion

; grp

4 (n

=

5): v

entra

l root

avuls

ion +

reim

-pla

ntati

on; g

rp 5

(n =

5): v

entra

l ro

ot av

ulsion

+

sura

l ner

ve gr

aft

impla

ntati

on

(tota

l: 15)

4 mg/

kgPo

stop,

daily

for w

k 1,

then

BID

for

wks 2

& 3

IP

Histo

path

ology

: rilu

zole

↑ mo

tor

neur

on su

rviva

l afte

r ven

tral

root

avuls

ion &

augm

ents

motor

ne

uron

al su

rviva

l & a

xona

l gr

owth

after

reinn

erva

tion

Beha

vior:

riluzo

le au

gmen

ts fu

nc-

tiona

l reco

very

in fo

relim

b afte

r re

inner

vatio

n in a

time-

delay

ed

mann

er

Kitzm

an,

2009

Effec

tiven

ess

of rilu

zole

in su

p-pr

essin

g spa

stic-

ity in

the s

pinal

cord

injur

ed ra

t

In viv

o cr

oss-

over

Rat

S2 sp

inal tr

an-

secti

on

Grp 1

(n =

10):

riluzo

le 8 m

g/kg

; grp

2 (n

=

9): s

aline

10 m

g/kg

(to

tal: 1

9)

Grp 1

(n =

10):

salin

e 8 m

g/kg

; gr

p 2 (n

= 9)

: sa

line 1

0 mg/

kg

(tota

l: 19)

8 or 1

0 mg

/kg

Once

daily

for 3

DPI

IP

Histo

path

ology

: rilu

zole

↑ mo

tor

neur

on su

rviva

l afte

r ven

tral

root

avuls

ion &

augm

ents

motor

ne

uron

al su

rviva

l & a

xona

l gr

owth

after

reinn

erva

tion

Beha

vior:

Tx w

/ both

8 &

10 m

g/kg

rilu

zole

↓ re

spon

se to

noxio

us

(pinc

h) &

nonn

oxiou

s (lig

ht tou

ch) s

timuli

, w/ 1

0 mg/

kg al

so

atten

uatin

g quic

k stre

tch re

flex

Ates

et

al.,

2007

Comp

arati

ve

neur

opro

tectiv

e ef

fect o

f sod

ium

chan

nel b

locke

rs

after

expe

rimen

-ta

l spin

al co

rd

injur

y

In viv

oRa

tW

eight-

drop

tra

uma a

t T7

–10 (

50 g

/cm

)

Grp 1

(n =

18):

riluzo

le Gr

p 1 (n

= 18

): sh

am; g

rp 2

(n =

18

): ve

hicle;

grp

3 (n =

18):

mexi-

letine

; grp

4 (n

=

18):

phen

ytoin

(tota

l: 72)

8 mg/

kg

Sing

le do

se po

stin-

jury

IP

Histo

path

ology

: rilu

zole

redu

ces

spina

l cor

d les

ion ar

ea, li

pid

pero

xidati

on, &

spina

l cor

d wa

ter co

ntent

Beha

vior:

riluzo

le im

prov

es m

otor

func

tion &

incli

ned p

lane s

core

Nógr

ádi

et al.

, 20

07

Delay

ed ri

luzole

tre

atmen

t is

able

to re

scue

inj

ured

rat s

pinal

moton

euro

ns

In viv

oRa

tL4

ventr

al ro

ot av

ulsion

+ re

-im

plant

ation

do

rsola

terall

y

Grp 1

(n =

5): in

jury +

rilu

zole

imme

di-ate

ly; gr

p 2 (n

= 5)

: inj

ury +

riluz

ole 5

DPI; g

rp 3

(n =

5):

injur

y + ri

luzole

10

DPI; g

rp 4

(n =

5):

injur

y + ri

luzole

14

DPI; g

rp 5

(n =

5):

injur

y + ri

luzole

16

DPI (

total:

25)

Grp 6

(n =

3): s

ham;

gr

p 7 (n

= 4)

: inj

ury +

no Tx

(to

tal: 7

)

4 mg/

kgIm

media

tely,

5, 10

, 14

, or 1

6 DPI

1st

dose

+ da

ily 1

wk

+ BI

D fo

r nex

t 2

wks

IP

Histo

path

ology

: ear

ly (10

DPI

&

befo

re) r

iluzo

le Tx

↑ m

otor

neur

on su

rviva

l com

pare

d w/

delay

ed (1

4 DPI

& af

ter) r

iluzo

le Tx

CONT

INUE

D ON

PAG

E 13

»

» CON

TINU

ED F

ROM

PAGE

11


Srinivas et al.


TABL

E 2.

Impa

ct o

f rilu

zole

on S

CI in

in vi

tro an

d in

vivo

anim

al ex

perim

ents

Auth

ors &

Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

el Ex

perim

enta

l Grp

Contr

ol Gr

pDo

seTi

ming

Route

Main

Find

ings

Sprin

ger

et al.

, 19

97

Rapid

calpa

in I

activ

ation

and

cytos

kelet

al pr

o-tei

n deg

rada

tion

follo

wing

trau

-ma

tic sp

inal c

ord

injur

y: at

tenua

-tio

n with

riluz

ole

pretr

eatm

ent

In viv

oRa

tCo

ntusio

n inj

ury (

impa

c-tor

prob

e at

T10)

Grp 1

(n =

6): S

CI +

rilu

zole

Grp 2

(n =

6): S

CI +

ve

hicle

8 mg/

kg15

mins

pre-

& 2

hrs

posti

njury

IPHi

stopa

tholo

gy: r

iluzo

le Tx

sign

ifi-ca

ntly ↑

MAP

2 lev

els, a

mar

ker

of str

uctur

al ne

uron

al int

egrit

y

Schw

artz

& Fe

h-lin

gs,

2001

Evalu

ation

of th

e ne

urop

rotec

tive

effec

ts of

sodiu

m ch

anne

l bloc

kers

af

ter sp

inal c

ord

injur

y: im

prov

ed

beha

viora

l and

ne

uroa

natom

ical

reco

very

with

rilu

zole

In viv

oRa

tCo

mpre

ssive

SC

I at C

7–T1

Grp 1

(n =

15):

riluzo

leGr

p 2 (n

= 15

): ve

hicle

5 mg/

kg15

mins

posto

pIP

Histo

path

ology

: rilu

zole

atten

uates

gr

ay m

atter

loss

rostr

ocau

dal

to ↑

injur

y epic

enter

; rilu

zole

at-ten

uates

norm

alize

d epic

enter

ca

vity a

rea;

riluzo

le ↑

red n

uclei

ne

uron

s cau

dal to

injur

yBe

havio

r: rilu

zole

signifi

cantl

y ↑

hindli

mb fu

nctio

n on B

BB sc

ale

& str

engt

h on i

nclin

ed pl

ane

scale

Mu e

t al.,

2000

39Ri

luzole

and m

eth-

ylpre

dniso

lone

comb

ined t

reat-

ment

impr

oves

fu

nctio

nal re

cov-

ery i

n tra

umati

c sp

inal c

ord i

njury

In viv

oRa

tNY

U im

pacto

rGr

p 1 (n

= 9)

: rilu

zole;

gr

p 2 (n

= 9)

: rilu

-zo

le +

methy

lpred

-nis

olone

(tot

al: 18

)

Grp 3

(n =

9):

vehic

le8 m

g/kg

2 & 4

hrs p

ostin

jury

IPHi

stopa

tholo

gy: r

iluzo

le w/

me

thylpr

ednis

olone

& no

t alon

e ca

uses

sign

ifican

t tiss

ue sp

ar-

ing at

lesio

n epic

enter

Beha

vior:

riluzo

le w/

meth

ylpre

d-nis

olone

↑ lo

como

tor fu

nctio

n in

open

field

test

Lips e

t al.,

2000

Neur

opro

tectiv

e ef

fects

of rilu

zole

and k

etam

ine

durin

g tra

nsien

t sp

inal c

ord i

s-ch

emia

in th

e ra

bbit

In viv

oRa

bbit

Aorti

c occ

lusion

w/

ballo

on

cath

eter

Grp 1

(n =

15):

injur

y +

riluzo

le; gr

p 2

(n =

15):

injur

y +

riluzo

le +

keta

mine

(to

tal: 3

0)

Grp 3

(n =

15):

injur

y + co

ntrol

8 mg/

kg15

mins

IV pr

einjur

y &

BID

IP fo

r 3 D

PIIV

& IP

Histo

path

ology

: rilu

zole

Tx ↑

moto

r ne

uron

s in v

entra

l hor

nBe

havio

r: rilu

zole

Tx re

duce

s ov

erall

neur

ologic

al de

ficits

&

para

plegia

incid

ence

, &

impr

oves

Tarlo

v sco

re

CONT

INUE

D ON

PAG

E 14

»

» CON

TINU

ED F

ROM

PAGE

12


Srinivas et al.


TABL

E 2.

Impa

ct o

f rilu

zole

on S

CI in

in vi

tro an

d in

vivo

anim

al ex

perim

ents

Auth

ors &

Ye

arTi

tleSt

udy

Desig

nSu

bject

Type

Injur

y Mod

el Ex

perim

enta

l Grp

Contr

ol Gr

pDo

seTi

ming

Route

Main

Find

ings

Lang

-Laz

-du

nski

et al.

, 20

0032

Ische

mic s

pinal

cord

injur

y ind

uced

by ao

rtic

cros

s-cla

mping

: pr

even

tion b

y rilu

zole

In viv

oRa

bbit

Dire

ct ao

rtic

arch

+ lt

subc

lavian

ar

tery c

ross

-cla

mping

Grp 1

(n =

15):

injur

y +

riluzo

leGr

p 2 (n

= 15

): no

inj

ury;

grp 3

(n

= 15

): inj

ury +

co

ntrol

(tota

l: 30)

4 mg/

kg30

mins

prein

jury &

at

onse

t of r

eper

-fu

sion

IVHi

stopa

tholo

gy: r

iluzo

le Tx

atten

u-ate

s red

uctio

n of M

AP2 l

evels

in

dors

al ho

rn &

inter

media

te zo

ne, r

educ

es ap

optos

is in

gray

ma

tter &

comp

letely

prev

ents

apop

tosis

in ve

ntral

horn

s as

meas

ured

by T

UNEL

stain

ing,

& re

duce

s fra

gmen

ting o

f DNA

Beha

vior:

riluzo

le Tx

↑ ne

urolo

gi-ca

l outc

omes

on M

SDI a

s ear

ly as

24 hr

s afte

r rep

erfu

sion

Lang

-Laz

-du

nski

et al.

, 20

0031

Prev

entio

n of

ische

mic s

pinal

cord

injur

y: co

m-

para

tive e

ffects

of

magn

esium

su

lfate

and

riluzo

le

In viv

oRa

bbit

Infra

rena

l aor

ta

occlu

sion f

or

40 m

ins

Grp 1

(n =

17):

riluzo

le be

fore

clam

ping;

grp 2

(n =

17):

MgS

O 4 +

riluz

ole

befo

re cl

ampin

g (to

tal: 3

4)

Grp 3

(n =

17):

vehic

le; gr

p 4 (n

=

15):

MgS

O 4

befo

re cl

ampin

g (to

tal: 3

2)

8 mg/

kgBe

fore

clam

ping

IVHi

stopa

tholo

gy: r

iluzo

le Tx

at-

tenua

tes ne

uron

al da

mage

&

pres

erve

s Map

2 exp

ress

ionBe

havio

r: rilu

zole

Tx ↑

Tarlo

v sc

ore a

s ear

ly as

24 hr

s afte

r re

perfu

sion

Mu e

t al.,

2000

39Ri

luzole

impr

oves

me

asur

es of

ox

idativ

e stre

ss

follo

wing

trau

-ma

tic sp

inal c

ord

injur

y

In viv

oRa

bbit

Contu

sion i

njury

(im

pacto

r rod

at

T10)

Grp 1

(n =

9): r

iluzo

le;

grp 2

(n =

9): r

ilu-

zole

+ me

thylpr

ed-

nisolo

ne (t

otal:

18)

Grp 3

(n =

9):

vehic

le; gr

p 4 (n

=

9): m

ethylp

red-

nisolo

ne (t

otal:

18

)

8 mg/

kg15

mins

& 2

hrs

posti

njury

IPHi

stopa

tholo

gy: r

iluzo

le Tx

alo

ne si

gnific

antly

↑ m

ito-

chon

drial

func

tion i

n syn

apto

-so

mes;

riluzo

le Tx

alon

e doe

s no

t sign

ifican

tly ↓

reac

tive

oxyg

en sp

ecies

; rilu

zole

Tx w

/ me

thylpr

ednis

olone

but n

ot alo

ne si

gnific

antly

redu

ces l

ipid

pero

xidati

on

BBB

= Ba

sso-

Beat

tie-B

resn

ahan

; EM

G =

electr

omyo

grap

hy; I

CV =

intra

cere

brov

entri

cular

; IT =

intra

thec

al; IV

= in

trave

nous

; mBB

B =

mod

ified B

BB; M

SDI =

moto

r sen

sory

defic

it ind

ex; N

YU =

New

Yor

k Univ

ersit

y.Tw

enty-

six st

udies

with

24 in

vivo

stud

ies, 1

in vi

tro st

udy,

and 1

comb

ined s

tudy

; 520

anim

als w

ere i

n the

riluz

ole tr

eatm

ent a

rm an

d 515

anim

als w

ere i

n com

para

tive c

ontro

l gro

ups.

» CON

TINU

ED F

ROM

PAGE

13


Srinivas et al.


TABL

E 3.

Impa

ct o

f rilu

zole

on S

CI in

hum

ans

Auth

ors

& Ye

arTi

tleSt

udy

Desig

n

No. o

f Pts

Rece

iving

Ri

luzole

No. o

f Pts

Rece

iving

Pl

aceb

oSC

I Lev

elAI

S Gr

ade

Aver

age

Age,

yrs

Dose

Timi

ngRo

uteAd

vers

e Ef

fects

Main

Find

ings

Mes

h- kini

et al.

, 20

18

Riluz

ole ca

n imp

rove

sen-

sory

and m

otor f

uncti

on in

pa

tients

with

acute

spina

l co

rd in

jury

Para

llel g

rp,

place

bo

con-

trolle

d

3030

NA40

% A

; 30

% B

; 30

% C

36.9

50 m

gBI

D fo

r 8 wk

s

PONA

Pts o

n rilu

zole

had ↓

pain

on

VAS

syste

m &

signifi

cantl

y les

s sev

ere S

CI as

deter

mine

d by

Fra

nkel

class

6 mo

s pos

topGr

oss-

man

et al.

, 20

14

A pr

ospe

ctive

, mult

icente

r, ph

ase I

matc

hed-

com

-pa

rison

grp t

rial o

f safe

ty,

phar

maco

kineti

cs, a

nd

preli

mina

ry ef

ficac

y of

riluzo

le in

patie

nts w

ith

traum

atic s

pinal

cord

Injur

y

Para

llel g

rp,

place

bo

con-

trolle

d

3636

77.8%

C4–

8; 13

.9%

T1–6

; 8.

3% T

7–12

52.8%

A;

25%

B;

22.2

% C

4050

mg

BID

for

28

days

PO, n

aso-

gastr

ic tub

e

14–7

0% ha

d ele

vatio

n of

liver

en

zyme

s &

biliru

bin

levels

Pts o

n rilu

zole

w/ ce

rvica

l SCI

ha

d sign

ifican

tly hi

gher

moto

r sc

ores

(ISN

CSCI

) tha

n con

-tro

ls 90

days

posto

p

Theis

s et

al.,

2011

Riluz

ole de

crea

ses fl

exion

wi

thdr

awal

refle

x but

not

volun

tary

ankle

torq

ue in

hu

man c

hron

ic sp

inal c

ord

injur

y

w/in

grp,

place

bo

con-

trolle

d

77 (

same

pts

)14

.3% C

1–4;

57.1%

C4–

8; 14

.3% T1

–6;

14.3%

T7–

12

35.7%

C;

64.3%

D44

50 m

gOn

cePO

None

Riluz

ole si

gnific

antly

↑ th

resh

old

stimu

lation

inten

sity &

aver

-ag

e sus

taine

d tor

que w

hile

↓ pe

ak am

plitu

de of

ankle

do

rsifle

xion t

orqu

e for

flexio

n wi

thdr

awal

resp

onse

; rilu

zole

does

not s

ignific

antly

chan

ge

mean

peak

torq

ue du

ring m

ax

volun

tary

contr

actio

n

ISNC

SCI =

Inte

rnat

ional

Stan

dard

s for

Neu

rolog

ical C

lassifi

catio

n of S

pinal

Cord

Injur

y; VA

S =

visua

l ana

log sc

ale.

Thre

e stu

dies w

ith co

rresp

ondin

g bas

eline

AIS

grad

e dist

ribut

ions o

f 42.

6% gr

ade A

, 25%

grad

e B, 2

6.6%

grad

e C, a

nd 6.

2% gr

ade D

.


Srinivas et al.


blocking presynaptic release of glutamate, and blocking persistent sodium currents.11 Of significance, in contrast to ALS where a high bioavailability (> 90%) is reported,9 riluzole in SCI in humans exhibited a lower maximum concentration and systemic exposure 0–12 hours after dos-ing.10 Even more importantly, in SCI, there is inflamma-tion, which increases the spinal cord expression of PgP, a drug efflux transporter, which decreases the bioavailability of riluzole in the spinal cord compared to plasma, so anti-inflammatory medications such as COX or LOX-5 inhibi-tors decrease PgP expression and increase bioavailability of riluzole in the spinal cord.15 However, other studies have suggested that the half-life of riluzole increases with SCI and remains substantially higher in the spinal cord than in the plasma.58 The effects of riluzole seem dose-dependent, with glutamatergic uptake activity of 0.1 and 1.0 mM rilu-zole in spinal cord synaptosomes that are not replicated at higher doses.2 Careful dose management is likely required for effective treatment of riluzole in humans. Moreover, in one pharmacological study, there was a 30% treatment-associated mortality with riluzole,15 suggesting that despite therapeutic benefits, conservative administration of rilu-zole in SCI is required for most optimal results.

Within the animal studies, there were significant thera-peutic benefits of riluzole manifested by increased tissue sparing,1,6,21,30,32,33,38,39,41,44,46–49,55,57,58 decreased neuropa-thy,5,24 improved motor function,1,7,21,27,32–34,38,44,47–49,55 and reduction of aberrant electrophysiology.5,47 Histological benefits of riluzole were often localized caudal to the inju-ry epicenter.34,47,48,55,58 Specifically, riluzole decreased mo-lecular markers of injury such as reactive oxygen species49 and immune cells,7,58 while preserving markers of plastic-ity and structural integrity such as MAP2,32,51 synapto-physin, and subunits of the NMDA receptor and AMPA receptor.47 This neuroprotective effect of riluzole was of-ten augmented by other pharmacological agents, such as methylprednisolone38,39 and dantrolene.34 Moreover, sev-eral studies demonstrated dose-dependent,5 time-depen-dent,41,46 and route-dependent24 efficacy of riluzole in SCI, suggesting that dose, timing, and route are important fac-tors to consider in clinical SCI. While studies demonstrate poor efficacy of riluzole in select experiments—behavior-ally,34 histologically,7,23,39,50,55 or via electrophysiological measurements46,50—no study exclusively reported negative results. Rather, the efficacy of riluzole can be subtherapeu-tic or inferior to other neuroprotective agents contingent on a variety of aforementioned factors.

Many studies produced negative results, with riluzole having little effect on outcomes. For example, one study showed that riluzole alone without methylprednisolone does not improve locomotion or tissue sparing.38 Likewise, another study showed that riluzole does not reduce apop-tosis or increase motor function or strength after SCI.7 A similar study showed that riluzole does not affect survival or the phenotype of cells after a neural stem and progeni-tor cell graft.23 Sámano et al.46 suggested that there is no change in peak amplitude of polysynaptic response to dor-sal root stimulation or reflex area in vivo, and no change in ventral motor neuron cell survival in vitro with riluzole. However, a variety of studies found the opposite with re-gard to ventral motor neuron cell survival.33,41,44 Mu et al.39

suggested that riluzole does not reduce reactive oxygen species or lipid deoxidation, but the opposite was found by Shimizu et al.49 and Ates et al.,1 respectively. Given the discrepancy in outcomes between animal studies, riluzole may be neuroprotective in SCI on a selective basis. For ex-ample, studies have shown that with higher doses, riluzole had longer-lasting and more effective outcomes.5,23 How-ever, also with high doses of riluzole, adverse outcomes such as death and respiratory distress have been reported.58

Of encouragement, early clinical studies suggested that riluzole is efficacious in decreasing neuropathic pain,37 increasing motor recovery,22 and decreasing aberrant re-flexes.54 However, given the relatively sparse number of pa-tients (n = 73) and potential hepatotoxic effects of riluzole22 in SCI, there remains a need for more robust clinical data on safety and therapeutic benefit from the phase 2 and 3 clinical trials.18 This is especially true considering the wide range of adverse effects reported with riluzole use in ALS, including hypertension, peripheral edema, pancreatitis,17 neutropenia, renal disease, interstitial lung disease, and hepatotoxicity. The use of riluzole in SCI is documented far more extensively in animal models than in humans. Given this disparity in total subjects, animal studies have greater power, and the neuroprotective effects of riluzole after SCI in animals are well known. As more patients are enrolled in the ongoing phase 2 clinical trial, the effects of riluzole on motor, sensory, and neurological function will become better understood.18 Thus, the primary limitation of this re-view includes extrapolation of animal data to the clinical efficacy of riluzole. Moreover, the most common adverse effects of riluzole are described more extensively in ALS than in SCI. According to the National Spinal Cord Injury Center, life expectancy for patients with SCI remains sig-nificantly lower than for those without SCI, and this dis-parity has not been improving since the 1980s.40 Given the astronomical inpatient and outpatient costs associated with SCI,20 improving patient outcomes with neuroprotective agents can decrease cost and improve quality of life.

ConclusionsThe neuroprotective effects of riluzole in SCI are prom-

ising, but the therapeutic benefit of riluzole in SCI must be appreciated in the appropriate clinical context. Success in animal models does not always translate to success in humans. While preliminary human studies suggest that riluzole may have a role in decreasing neuropathic pain and improving motor recovery for patients with SCI, there remains a need to substantiate these data with consistent-ly reported clinical studies. However, other studies have demonstrated adverse effects, including pancreatitis, lung disease, and neutropenia, without conferring much clini-cal benefit. As the drug advances through the subsequent clinical trial stages, it will be important to titer the dose and timing to maximize benefits in appropriately select-ed patients to minimize adverse or ineffective outcomes. Nevertheless, these efforts provide the opportunity to ex-pand the existing, limited pharmacological treatment op-tions to mitigate the devastating effects of SCI and to offer patients the possibility of medical options to improve long-term function and pain control.


Srinivas et al.


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DisclosuresThe authors report no conflict of interest concerning the materi-als or methods used in this study or the findings specified in this paper.

Author ContributionsConception and design: all authors. Acquisition of data: Srini-vas. Analysis and interpretation of data: all authors. Drafting the article: all authors. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Pham. Statistical analysis: all authors. Administrative/technical/material support: Pham. Study supervision: Pham.

CorrespondenceMartin H. Pham: University of California San Diego School of Medicine, San Diego, CA. [email protected].


department of neurosurgery, university of california san ... · department of neurosurgery,...

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