Cerebrolysin

Cerebrolysin: what the published research shows

Compiled by NADA-Labs from the peer-reviewed literature cited below. No own study data.

Cerebrolysin is not a single peptide but a preparation produced by enzymatic breakdown of purified porcine brain proteins (Ladurner 2005, PMID 15583955; Ziganshina 2023, PMID 37818733); based on total nitrogen content it consists of about 25 % low-molecular-weight peptides (< 10 kDa) and about 75 % free amino acids⁷. The research literature attributes its effects mainly to an activity resembling that of neurotrophic factors⁶ — reduced apoptosis of cultured neurons, which the authors assign to the peptide fraction⁷, neurite outgrowth in sensory and sympathetic neurons (Satou 2000, PMID 11145001) and increased neurogenesis after experimental stroke, with progenitor-cell proliferation depending on the PI3K/Akt pathway⁶. It has been studied in chick neuron cultures⁷, in rats with embolic stroke and in their neural progenitor cells⁶, and in randomised, double-blind, placebo-controlled trials in acute ischaemic stroke^2,5, early rehabilitation after stroke¹, vascular dementia³ and Alzheimer’s disease⁴.

Evidence base: Five randomised, double-blind, placebo-controlled human trials (n = 119 to 1070) — three in stroke^1,2,5 and two in dementia^3,4 — plus one study in rats and rat progenitor cells⁶ and one in chick neuron cultures⁷. Further randomised trials cover acute stroke (Ladurner 2005, PMID 15583955) and mild to moderate Alzheimer’s disease (Ruether 2001, PMID 11552768; Alvarez 2006, PMID 16420392). A 2023 Cochrane review included seven randomised trials in acute ischaemic stroke with 1773 participants, one of which tested a different peptide mixture (Ziganshina 2023, PMID 37818733). CARS was funded by the manufacturer of the studied preparation¹; the other trial abstracts contain no funding statement. The preclinical data summarised here come from one rat study⁶ and two chick cell-culture studies⁷ (Satou 2000, PMID 11145001).

Key studies at a glance

Safety outcomes reported in CARS (Muresanu 2016 [S1])

Effects reported in the studies

• Upper-limb motor recovery after stroke. In CARS (n = 208; 205 analysed on day 90), patients in early rehabilitation after ischaemic stroke reached a mean ARAT score of 40.7 on day 90 with Cerebrolysin vs 26.5 with placebo (baseline 10.1 vs 10.7), a mean change of 30.7 vs 15.9 points; the Mann-Whitney estimator for ARAT on day 90 was 0.71 (95 % CI 0.63-0.79; p < 0.0001) and 0.62 (95 % CI 0.58-0.65) for global status across 12 outcome scales¹.
• Acute ischaemic stroke: primary and subgroup results. In CASTA (n = 1070; 529 vs 541) the combined primary end point showed no significant difference between groups; in a post hoc analysis of patients with NIHSS > 12 there was a trend in favour of Cerebrolysin (odds ratio 1.27 for NIHSS and for mRS, lower confidence bounds 0.97 and 0.90) and a cumulative 90-day mortality of 20.2 % with placebo vs 10.5 % with Cerebrolysin (hazard ratio 1.9661, lower confidence bound 1.0013)². In a further trial (n = 146), the Canadian Neurological Scale, Barthel Index and Clinical Global Impressions did not differ significantly, while the Syndrome Short Test of cognitive function did (Ladurner 2005, PMID 15583955).
• Neurological response with thrombolysis. In 119 patients treated with alteplase within 3 h of symptom onset, the third interim analysis showed no benefit on the mRS at day 90 and the trial was stopped; in the secondary NIHSS responder analysis, significantly more patients in the Cerebrolysin group improved by 6 or more points (or reached a total score of 0 or 1) on days 2, 5, 10 and 30, and mRS responder trends were not significant⁵.
• Cognition and global function in vascular dementia. In 242 patients, ADAS-cog+ improved by 10.6 points with Cerebrolysin vs 4.4 points with placebo at week 24 (least-squares mean difference -6.17, p < 0.0001) and the mean CIBIC+ score was 2.84 vs 3.68 (treatment difference 0.84, p < 0.0001); responder rates were 82.1 % vs 52.2 % (ADAS-cog+ improvement of at least 4 points), 75.3 % vs 37.4 % (CIBIC+ score below 4) and 67.5 % vs 27.0 % (combined), with odds ratios of 5.08 and 5.63 for a favourable CIBIC+ and combined response³.
• Global function and cognition in Alzheimer’s disease. In 192 patients, CIBIC+ at week 12 differed significantly in favour of Cerebrolysin (p = 0.033), with 76 % vs 57 % responders (score of 4 or lower, p = 0.007), while the Disability Assessment in Dementia and the Cornell Depression Scale showed trends only; the groups differed at baseline in age, age at onset of dementia and hallucinations⁴. A 28-week trial (n = 149) reported CGI responders of 63.5 % vs 41.4 % at week 16 and an ADAS-cog difference of 3.2 points (Ruether 2001, PMID 11552768); a 24-week trial with three dose groups (n = 279) reported significant global improvement in all three but a significant ADAS-cog effect only in the lowest dose group, which the authors describe as a reversed U-shaped dose-response (Alvarez 2006, PMID 16420392).
• Neurogenesis and apoptosis after experimental stroke (rat). In rats with embolic middle cerebral artery occlusion, treatment started 24 h after stroke increased BrdU+ progenitor cells and DCX+ migrating neuroblasts in the ipsilateral SVZ and the striatal ischaemic boundary at day 28 in the two higher dose groups and reduced TUNEL+ cells by about 50 % in the ischaemic boundary but not in the SVZ; infarct volume was not significantly reduced, while performance in a battery of behavioural tests improved on days 21 and 28⁶.
• Progenitor-cell proliferation via PI3K/Akt (in vitro). SVZ neural progenitor cells from ischaemic rats showed 43.6 % vs 27.1 % BrdU+ cells with Cerebrolysin vs control (n = 6), an increase abolished by the PI3K inhibitor LY294002 (29.7 %); the preparation also increased Tuj1+ immature neurons and promoted progenitor-cell migration⁶.
• Neuronal survival and neurite outgrowth (cell culture). In embryonic chick cortical neurons under low-serum stress, Cerebrolysin reduced the share of cells with apoptotic chromatin changes (p < 0.01) and improved viability after 8 days in vitro, whereas an artificial mixture of the free amino acids did neither; after 4 days both increased viability to a similar extent⁷. In chick embryo explants it promoted neurite outgrowth in dorsal root ganglion and sympathetic neurons, less markedly than nerve growth factor and with an inverted-U concentration relationship, but not in ciliary ganglion neurons (Satou 2000, PMID 11145001).

Adverse effects and tolerability reported

• Adverse events in CARS. At least one adverse event was reported by 69.2 % with Cerebrolysin vs 71.2 % with placebo, most of them mild (76.1 % vs 69.8 % of events); serious adverse events occurred in 3 (2.9 %) vs 7 (6.7 %) patients, none of which appeared related to the study medications; no patient died in the Cerebrolysin group vs 4 (3.8 %) in the placebo group, and 2 vs 5 patients discontinued because of adverse events¹.
• Pooled stroke trials (Cochrane review). Cerebrolysin or a similar peptide mixture probably made little to no difference in all-cause death (risk ratio 0.96, 95 % CI 0.65-1.41; 6 trials, 1689 participants) and Cerebrolysin in the total number of people with serious adverse events (risk ratio 1.16, 95 % CI 0.81-1.66; 3 trials, 1335 participants), but the number of people with non-fatal serious adverse events increased (risk ratio 2.39, 95 % CI 1.10-5.23; moderate-certainty evidence); the total number of people with adverse events showed little to no difference (risk ratio 1.03, 95 % CI 0.92-1.14; 4 trials, low-certainty evidence) (Ziganshina 2023, PMID 37818733).
• Adverse events in the Alzheimer’s trials. Adverse events were recorded in 64 % with Cerebrolysin vs 73 % with placebo, most commonly headache, dizziness, weight loss and anxiety⁴; a 28-week trial reported 43 % vs 38 % (Ruether 2001, PMID 11552768), and a trial with three dose groups reported similar rates across all groups (Alvarez 2006, PMID 16420392).
• Combination with thrombolysis. In 119 patients treated with alteplase, adverse events did not differ between the treatment groups; the abstract gives no event rates⁵.
• Trials without adverse-event figures in the abstract. CASTA documented adverse events but reports no frequencies in its abstract², and the vascular dementia trial gives only the summary statement that the preparation was well tolerated³; in a further acute-stroke trial adverse events occurred with similar frequency in both groups (Ladurner 2005, PMID 15583955).
• Preclinical studies and research material. The rat and cell-culture studies report no toxicology or safety end points^6,7; none of the cited studies examined lyophilised research material.

Limitations of the evidence. Cerebrolysin is a multicomponent mixture of peptides and free amino acids⁷, and all human trials gave the studied preparation intravenously^1,2,3,4,5; none of the cited studies examined lyophilised research material or established that other preparations are equivalent. Results in stroke are mixed: the primary end points of CASTA and of the alteplase trial were not met, the CASTA mortality difference comes from a post hoc subgroup without stated subgroup size in the abstract^2,5, and CARS was an exploratory phase II trial whose authors call for confirmation in a large-scale trial¹. Besides the funding of CARS described above¹, the Cochrane review reports manufacturer support for three multicentre trials, a high risk of bias for incomplete outcome data in four trials and an unclear risk of selective outcome reporting across the Cerebrolysin trials (Ziganshina 2023, PMID 37818733). The dementia results cited here come from single trials with rating-scale end points, one with baseline differences between groups⁴ and one with a reversed U-shaped pattern across dose groups (Alvarez 2006, PMID 16420392). The preclinical findings cited here come from single studies in rats and chick neurons^6,7. None of the findings summarised here establish efficacy or safety for any use outside the described research models.

References

1. Muresanu DF, Heiss WD, Hoemberg V, Bajenaru O, Popescu CD, Vester JC, Rahlfs VW, Doppler E, Meier D, Moessler H, Guekht A (2016). Cerebrolysin and Recovery After Stroke (CARS): A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial. Stroke. PMID 26564102 DOI human study
2. Heiss WD, Brainin M, Bornstein NM, Tuomilehto J, Hong Z; Cerebrolysin Acute Stroke Treatment in Asia (CASTA) Investigators (2012). Cerebrolysin in patients with acute ischemic stroke in Asia: results of a double-blind, placebo-controlled randomized trial. Stroke. PMID 22282884 DOI human study
3. Guekht AB, Moessler H, Novak PH, Gusev EI; Cerebrolysin Investigators (2011). Cerebrolysin in vascular dementia: improvement of clinical outcome in a randomized, double-blind, placebo-controlled multicenter trial. Journal of Stroke and Cerebrovascular Diseases. PMID 20656516 DOI human study
4. Panisset M, Gauthier S, Moessler H, Windisch M; Cerebrolysin Study Group (2002). Cerebrolysin in Alzheimer’s disease: a randomized, double-blind, placebo-controlled trial with a neurotrophic agent. Journal of Neural Transmission. PMID 12111446 DOI human study
5. Lang W, Stadler CH, Poljakovic Z, Fleet D; Lyse Study Group (2013). A prospective, randomized, placebo-controlled, double-blind trial about safety and efficacy of combined treatment with alteplase (rt-PA) and Cerebrolysin in acute ischaemic hemispheric stroke. International Journal of Stroke. PMID 23009193 DOI human study
6. Zhang C, Chopp M, Cui Y, Wang L, Zhang R, Zhang L, Lu M, Szalad A, Doppler E, Hitzl M, Zhang ZG (2010). Cerebrolysin enhances neurogenesis in the ischemic brain and improves functional outcome after stroke. Journal of Neuroscience Research. PMID 20857512 DOI
7. Hartbauer M, Hutter-Paier B, Skofitsch G, Windisch M (2001). Antiapoptotic effects of the peptidergic drug cerebrolysin on primary cultures of embryonic chick cortical neurons. Journal of Neural Transmission. PMID 11475013 DOI

This section summarises findings published in the cited peer-reviewed literature for informational purposes. It is not a claim of efficacy or safety, contains no dosing or administration information by design, and does not constitute medical, veterinary or scientific advice. Results in cell cultures or animal models do not predict effects in humans.