Cerebrolisina

Dr. Luis Enrique Amaya Sánchez

Isquemia Cerebral

• Depende de 3 factores:

– Intensidad de la isquemia

– Duración de la isquemia

– Presencia de circulación colateral

Estrategias manejo Infarto Cerebral

• Neuroprotección

– Intenta reducir tamaño de la lesión isquémica en la fase aguda

• Neurorreparación

– Dirigida a restaurar el daño cerebral ya establecido

• “En la actualidad no se cuenta con un neuroprotector que haya demostrado su eficacia en estudios clínicos controlados”

Cantú C, Chiquete E. Clínicas Mexicanas de Neurologia. (1) 2012

Factores que influyen sobre las terapias restauradoras

• Ventana terapéutica

• Factores ambientales

• Experiencia

• Genética

• Factores que influyen negativamente

JAMA 2006;296

Cerebrolisina

• Péptido con acción similar a la de los factores neurotróficos

• Propiedades neuroprotectoras:

– Incrementa número de sinapsis

– Estímula células progenitoras neuronales

– Promueve migración células progenitoras hacia la zona isquémica

– En modelos animales reduce hasta el 65% del infarto cerebral

• Los factores neurotróficos son las moléculas endógenas más importantes involucradas en la protección y en la recuperación cerebral

Neurotrophic pathway of Cerebrolysin –

a multimodal action

Receptors

Shh/kinases

Therapeutic effects:NeuroprotectionNeurorestoration

Support of self-recovery mechanisms

NTFs

Genes expression

Cerebrolysin

Mimetic - direct pathway

Stimulation of NTFs production

- indirect pathway

Sonic Hedgehog Signaling Pathway MediatesCerebrolysin-Improved Neurological Function After

StrokeLi Zhang, MD; Michael Chopp, PhD; Dieter H. Meier, MD; Stefan Winter, PhD; LeiWang, MD; Alexandra Szalad, MS; Mei Lu, PhD; Min Wei, BS; Yisheng Cui, MD; ZhengGang Zhang, MD, PhD

Background and Purpose—Cerebrolysin, a mixture of neurotrophic peptides, enhances neurogenesis and improvesneurological outcome in experimental neurodegenerative diseases and stroke. The Sonic hedgehog (Shh) signalingpathway stimulates neurogenesis after stroke. The present study tests whether the Shh pathway mediatescerebrolysininduced neurogenesis and improves neurological outcome after stroke.Methods—Rats subjected to embolic stroke were treated with cerebrolysin with or without cyclopamine.Results—Using neural progenitor cells derived from the subventricular zone of the lateral ventricle of adult rats, wefound that cerebrolysin significantly increased neural progenitor cells proliferation and their differentiation intoneurons and myelinating oligodendrocytes, which were associated with upregulation of Shh and its receptors patchedand smoothened. Blockage of the Shh signaling pathway with a pharmacological smoothened inhibitor, cyclopamine, abolished cerebrolysin-induced in vitro neurogenesis and oligodendrogenesis. In the ischemic rats, treatment withcerebrolysin starting 24 hours after stroke significantly increased neural progenitor cell proliferation in thesubventricular zone and enhanced neurogenesis, oligodendrogenesis, and axonal remodeling in the peri-infarct area. Moreover, profound neurological function improvements were observed in rats treated with cerebrolysin from week 3 to week 5 after stroke onset compared with vehicle-treated rats. However, in vivo inhibition of the Shh pathway withcyclopamine completely reversed the effects of cerebrolysin on neurorestoration and functional recovery.Conclusions—These results demonstrate that the Shh pathway mediates cerebrolysin-enhanced neurogenesis andwhite matter remodeling and improves functional recovery in rats after stroke.

Stroke. 2013;44:00-00

Cerebrolisina en la terapia del stroke

Evidencia clínica

•10 estudios randomizados, doble ciego, placebo controlado

•Cerebrolisina utilizado de forma concomitante a la terapia básica, estándar del infarto cerebral, comparado con placebo o sólo terapia estándar

•N=2228 patientes enrolados

•Estudios pequeños en cuanto a número de pacientes

Cerebrolysin adjuvant treatment in Broca’s aphasics following firstacute ischemic stroke of the left middle cerebral artery

Dragos Catalin Jianu, Dafin Fior Muresanu, Ovidiu Bajenaru, Bogdan Ovidiu Popescu, SandaMaria Deme.

Journal of Medicine and Life Vol. 3, No.3, July‐September 2010, pp.297‐307

Background: The aim of our study was to assess the efficacy of Cerebrolysin administration in Broca’s aphasics with acuteischemic stroke.Methods: We registered 2,212 consecutive Broca’s aphasics following an acute ischemic stroke admitted in fourdepartments of neurology in Romania, between September 2005 and September 2009. Language was evaluated with theRomanian version of the Western Aphasia Battery (WAB). The following inclusion criteria were used for this study: age 20-75 years, admission in the hospital within 12 hours from the onset of the symptoms, diagnosis of first acute left middlecerebral artery (MCA) ischemic stroke, presence of large artery disease (LAD) stroke, a NIHSS score of 5-22 points, and atherapeutic time window within 72 h. Fifty two patients were treated with Cerebrolysin (Cerebrolysin group) as anadjunctive treatment. A placebo group, which received saline infusions (n=104 patients) were matched to the NIHSS andWAB scores, gender and age of the Cerebrolysin group at baseline. We assessed spontaneous speech (SS), comprehension(C), repetition (R), naming (N), and Aphasia Quotient (AQ) scores of the two groups in an open label design, over 90 days,the mRS scores and mortality.Results: The Cerebrolysin and the placebo groups had similar age (66+/-8 versus 65+/-8 years) and sex ratio (14/38 versus30/74). The mean AQ scores and the mean subscores for 3 subtests of WAB (SS, R, N) were similar at baseline and improvedin the Cerebrolysin group significantly (p<0.05) over placebo group at all study time points. The mRS score at 90 days wasalso lower in the Cerebrolysin group than in the placebo group. Cerebrolysin and placebo were both tolerated and safe, andno difference in the mortality rate was seen (3.8% in each group).Conclusion: Cerebrolysin is effective for the treatment of Broca’s aphasics with a first acute ischemic stroke of the leftMCA territory.

Journal of Medicine and Life Vol. 3, No.3, July‐September 2010, pp.297‐307

A prospective, randomized, placebo-controlled,double-blind trial about safety and efficacy of

combined treatment with alteplase (rt-PA) andCerebrolysin in acute ischaemic hemispheric stroke

Wilfried Lang, Christian H. Stadler, Zdravka Poljakovic, David Fleet ,and the Lyse Study Group

International Journal of Stroke © 2012 World Stroke Organization Vol8, February 2013, 95–104

Cerebrolisina apoya la reperfusión

• Evolution of the National Institutes of Health Stroke Scale (NIHSS) responders for the Cerebrolysin and placebo groups. Defined as improvement of at least 6 points from baseline or total score 0-1. *p<0.05 vs. placebo (30 ml/10 days; immediately after rtPA).

Strongest Cerebrolysin treatment effect

around day 7 post-stroke

Cerebrolisina y movilización temprana

Improvement of motor functionsafter stroke. Mean change frombaseline in the Canadian Neurological Scale (CNS) for the Cerebrolysin and placebo groups.

Shown is overlap with time window for EM

Cerebrolisina en Pacientes de Asia con Accidente Cerebrovascular Isquémico Agudo

Resultados de un Estudio Aleatorio, Doble Ciego, Placebo Controlado

Wolf-Dieter Heiss, MD*; Michael Brainin, MD; Natan M. Bornstein, MD; Jaakko Tuomilehto, MD, MPolSc, PhD; Zhen Hong, MD*; Investigadores en Asia para

el Tratamiento de Accidente Cerebrovascular Agudo con Cerebrolisina (CASTA)

Stroke. 2012;43:630-636

Cerebrolisina y movilización temprana

• Significant increase in survival rate in Cerebrolysin-treated sub-group with baseline NIHSS>12. Patients were treated for 10 days with a daily dosage of 30 ml.

Shown is overlap with time window for EM

Cerebrolisina en la terapia del infarto

cerebral

Los resultados indican efectos benéficos del tratamiento en los pacientes más severamente afectados (NIHSS >12)

-> ceiling effect in milder cases

CASTA trial: n=1070Hong et al., 2009Heiss et al., 2012

-6

-5

-4

-3

-2

-1

0

1 2 5 10 30 90

Ch

ange

fro

mB

ase

line

Day

NIHSS baseline ≤7

Cerebrolysin

Placebo

-6

-5

-4

-3

-2

-1

0

1 2 5 10 30 90C

han

ge f

rom

Bas

elin

e

Day

NIHSS baseline >12

Cerebrolysin

Placebo

Cerebrolisina en la terapia del infarto

cerebral

Los resultados indican reduccion de la mortalidad

CASTA trial: n=1070Hong et al., 2009Heiss et al., 2012

HR 1.26; 97.5% CI-LB 0.75

Cumulated mortality:Placebo 6.6%Cerebrolysin 5.3%

∆ = 1.3%

Cerebrolisina en la terapia del infarto

cerebral

Los resultados son más destacados en pacientes severamente afectados (NIHSS >12)

CASTA trial: nNIH>12=252Hong et al., 2009Heiss et al., 2012

HR 1.97; 97.5% CI-LB 1.00

Cumulated mortality:Placebo 20.2%

Cerebrolysin 10.5%

∆ = 9.7%

Cerebrolisina en la terapia del infarto

cerebral

El beneficio se observan tempranamente en el curso del tratamiento

Lysis trial: n=119Lang et al., 2012

Percentage of responders:

Cerebrolysin treatment phase

Responder definitions:mRS: score of 0 or 1 NIHSS: score of 0 or 1 BI: score of ≥95

or >6 points improvement

Conclusiones

La neuroprotección en el infarto cerebral requiere ser preventiva

•Comenzar de forma temprana durante la fase aguda

•La estimulación de la recuperación debe ser iniciada tempranamente

•Buscar fármacos cuyo efecto sea multimodal

•Cerebrolisina es segura y de efecto multimodal

•Se requiere diseño de estudios propios y definir la dosis ideal