Cerebrolysin

Cerebrolysin is a mixture of peptides purified from pig brains and is approved in many European and Asian countries for the treatment of stroke, traumatic brain injury and dementia; however it is not approved for use in the United States. It appears safe for short-term use (up to 3 years) and results from several clinical trials suggest it might offer small improvements to symptoms of Alzheimer’s disease and vascular dementia. It remains unknown if Cerebrolysin might prevent dementia, slow aging or lower risk of mortality.

EFFICACY
Possibly
with   Very limited  evidence
SAFETY WHEN
USED AS DIRECTED
Probably
with   Strong  evidence

Cerebrolysin is a mixture of peptides (short proteins and protein fragments) isolated from pig brains. Among other things, Cerebrolysin contains two peptides thought to be neuroprotective: brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which cross the blood-brain barrier (BBB) after injection and exert multiple protective benefits in the brain. Cerebrolysin must be injected, usually intravenously. While it is currently approved in 44 countries, mostly in Europe and Asia, it is not yet approved in the United States.  In other countries, it is used to treat stroke, although results from a recent multi-center, placebo-controlled clinical trial casts doubts on its usefulness in stroke treatment, except perhaps in cases of severe stroke [1]. It is important to note, however, that despite being advocated for more than 20 years for the treatment of Alzheimer’s disease and dementia, Cerebrolysin has not been convincingly shown to benefit these diseases.

Did You Know? While it may seem strange to inject molecules purified from pigs into our bodies, before scientists could synthetically make it, most insulin used to treat patients with diabetes was purified from pigs!

Cerebrolysin is purified from pig brains and is manufactured by Ebewe Pharmaceutical and Hangzhou Huaijin Pharmaceuticals. Although Ebewe does not offer concentration information for the Cerebrolysin it sells, Hangzhou Huaijin’s website states a content of 30-40mg amino acids/ml. It is widely-available without a prescription 44 countries and can be purchased online. While it is not approved for use in the United States, it can still be obtained through online retailers. It can be purchased for between $60 and $90 per 25ml and must be injected.

Possibly, based on very limited evidence.

Although Cerebrolysin has never been tested in a dementia prevention paradigm in humans and there is no observational data on its use in people at risk of dementia, preclinical data suggest it hypothetically may be useful in preventing dementia.

Possibly, based on limited evidence.

A 2007 meta-analysis of 6 clinical trials concluded that Cerebrolysin appeared to improve the ratings of patients with mild-to-moderate AD in the Global Clinical Impressions scale, which some experts believe to be subjective because it requires physicians to “rate” areas of patient functioning compared to healthy patients instead of using more objective measures of cognition and functioning. These results seem promising, but, as the authors concluded, more trials are necessary to fully evaluate Cerebrolysin’s effect of cognition and functioning [11]. However, some interesting areas of concordance are evident when examining the trials analyzed by this meta-analysis. The standard treatment in these trials (for patients with mild-to-moderate AD) is daily infusion of 30 ml Cerebrolysin for 4 weeks [12-14] although some trials lasted for 6 weeks [15] or treated for 4 weeks then another 4 weeks after an 8 week break [16]. The percent of patients who responded to the treatment were on average 25 to 30% higher in treatment than placebo groups with all trials reporting similar rates of adverse events between treatment and placebo groups. All trials reported significant improvements on Global Clinical Impressions scale; however, some trials reported improvements in more objective measures of cognition and activities of daily living (a functional assessment) and some did not.

Cerebrolysin also may be effective at treating symptoms of vascular dementia. A 2013 Cochrane analysis of 6 randomized clinical trials, some of which lasted for 3 years, comprising nearly 600 patients concluded that Cerebrolysin treatment improved clinical symptoms compared to placebo or no treatment, with very few reported side effects. While the measured improvements were statistically significant, they degree of improvement was small and may not be clinically significant (i.e. it may not improve functioning enough to be meaningful). Additionally, because of the small number of trials and the lack of long-term follow-up study, the Cochrane group concluded there was insufficient evidence to recommend it for routine treatment of vascular dementia [17].

A 4-month trial from Russia comparing the effectiveness of Cerebrolysin treatment to the Exelon™ patch (rivastigmine, an acetylcholinesterase inhibitor) reported a 1.7-fold higher response rate to Cerebrolysin than Exelon™. The clinical effectiveness of Cerebrolysin was estimated to be 6.5-fold greater than the Exelon™ patch [18]. However, this study was published only in Russian so we are unable to critically review it. Results from a study that used escalating doses [19] suggest doses higher than 30ml per day may have decreased efficacy. A comparative effectiveness study suggests that Cerebrolysin may be as effective as donepezil and may have additive benefits when used in combination with donepezil for treating AD symptoms [20].  These results have not, however, been confirmed yet in larger, randomized, well-controlled trials.

APOE4 Carriers: The trial mentioned above that compared the Exelon™ patch with Cerebrolysin found no differences in response rate in patients with at least one APOE4 allele but a 3-fold higher response rate in patients without an APOE4 allele. For more information on what the APOE gene means for your health, visit our APOE4 information page.

Unknown, given there is no evidence.

There is no evidence yet that Cerebrolysin slows age-related processes or extends lifespan.

Preclinical studies in test tubes and animal models have demonstrated multiple potential mechanisms of action for Cerebrolysin. Cerebrolysin protects cultured neurons and brain slices from damage from low-oxygen environments [2-4] as well as reducing inflammation [5] and promoting the formation of new neural connections (synapses) [6]. Additionally, Cerebrolysin appears to protect cognition and prevent detrimental behavior changes in mice engineered to get Alzheimer’s and in diabetic rats [7,8]. Cerebrolysin also reduced beta-amyloid plaques by regulating the production of beta-amyloid in a mouse model of AD [9] and reduced hyperphosphorylated toxic tau in a mouse model of frontotemporal dementia (FTD) [10].

Probably safe, based on strong evidence.

NOTE: This is not a comprehensive safety evaluation or complete list of potentially harmful drug interactions. It is important to discuss safety issues with your physician before taking any new supplement or medication.

Results from multiple clinical trials suggest it is safe for use up to 3 years with few adverse effects that are usually transient and include headaches, weight loss, dizziness, anxiety, agitation and feeling hot [21]. It appears that Cerebrolysin must be administered by intravenous injection daily, 5-times per week for up to 4 weeks to achieve effects, at a dose of 30 ml and that higher doses may be less effective [19]. There is very little information on potential harmful interactions with other medications; however, the decision to begin Cerebrolysin treatment should be carefully discussed with your healthcare provider. Because Cerebrolysin is purified from animal tissue, there is a risk of bacterial, viral or fungal contamination of the product. Additionally, the process of injecting Cerebrolysin, or anything for that matter, also carries some risks, including infection. Because of this and other risks, anyone considering Cerebrolysin should consult with their physician.

Before taking Cerebrolysin, you should consult with your primary physician. It is important to note that Cerebrolysin is not approved in the United States for the treatment of any condition. Available data suggest it must be administered by intravenous infusion daily, 5-times per week for up to 4 weeks to achieve effects, at a dose of 30 ml, while higher doses may be less effective [19]. The concentration of amino acids may vary by manufacturer. There is no available information of optimal concentrations for human use. Ebewe has supplied most of the Cerebrolysin used thus far in clinical trials and does not report information about the concentration of amino acids in this product. Additionally, the process of injecting Cerebrolysin, or anything for that matter, also carries some risks, including infection. Because of this and other risks, anyone considering Cerebrolysin should consult with their physician.

Several clinical trials are planned or on-going to evaluate Cerebrolysin’s potential to treat Alzheimer’s disease and traumatic brain injury. A head-to-head comparison trial between donepezil and Cerebrolysin will soon begin recruiting Alzheimer’s patients  (NCT01822951) while two trials currently recruiting patients to test whether Cerebrolysin can the recovery from traumatic brain injury (NCT02116348 and NCT01606111). Several other trials are studying Cerebrolysin as a potential treatment to preserve brain function after stroke or brain aneurism (NCT01996761 and NCT01787123).

For more information about how Cerebrolysin might help vascular dementia, read this 2013 Medscape article.

1. Heiss, W.D., et al., Cerebrolysin in patients with acute ischemic stroke in Asia: results of a double-blind, placebo-controlled randomized trial. Stroke, 2012. 43(3): p. 630-6.

2. Gutmann, B., et al., In vitro models of brain ischemia: the peptidergic drug cerebrolysin protects cultured chick cortical neurons from cell death. Neurotox Res, 2002. 4(1): p. 59-65.

3. Hutter-Paier, B., E. Steiner, and M. Windisch, Cerebrolysin protects isolated cortical neurons from neurodegeneration after brief histotoxic hypoxia. J Neural Transm Suppl, 1998. 53: p. 351-61.

4. Schauer, E., et al., Neuroprotection of cerebrolysin in tissue culture models of brain ischemia: post lesion application indicates a wide therapeutic window. J Neural Transm, 2006. 113(7): p. 855-68.

5. Alvarez, X.A., et al., Cerebrolysin reduces microglial activation in vivo and in vitro: a potential mechanism of neuroprotection. J Neural Transm Suppl, 2000. 59: p. 281-92.

6. Hartbauer, M., B. Hutter-Paie, and M. Windisch, Effects of Cerebrolysin on the outgrowth and protection of processes of cultured brain neurons. J Neural Transm, 2001. 108(5): p. 581-92.

7. Georgy, G.S., et al., Cerebrolysin Ameloriates Cognitive Deficits in Type III Diabetic Rats. PLoS One, 2013. 8(6): p. e64847.

8. Rockenstein, E., et al., The neuroprotective effects of Cerebrolysin in a transgenic model of Alzheimer's disease are associated with improved behavioral performance. J Neural Transm, 2003. 110(11): p. 1313-27.

9. Rockenstein, E., et al., Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease. J Neurosci Res, 2006. 83(7): p. 1252-61.

10. Rockenstein, E., et al., Cerebrolysin efficacy in a transgenic model of tauopathy: role in regulation of mitochondrial structure. BMC Neurosci, 2014. 15: p. 90.

11. Wei, Z.H., et al., Meta-analysis: the efficacy of nootropic agent Cerebrolysin in the treatment of Alzheimer's disease. J Neural Transm, 2007. 114(5): p. 629-34.

12. Bae, C.Y., et al., A double-blind, placebo-controlled, multicenter study of Cerebrolysin for Alzheimer's disease. J Am Geriatr Soc, 2000. 48(12): p. 1566-71.

13. Panisset, M., et al., Cerebrolysin in Alzheimer's disease: a randomized, double-blind, placebo-controlled trial with a neurotrophic agent. J Neural Transm, 2002. 109(7-8): p. 1089-104.

14. Ruther, E., et al., Efficacy of the peptidergic nootropic drug cerebrolysin in patients with senile dementia of the Alzheimer type (SDAT). Pharmacopsychiatry, 1994. 27(1): p. 32-40.

15. Muresanu, D.F., et al., Improved global function and activities of daily living in patients with AD: a placebo-controlled clinical study with the neurotrophic agent Cerebrolysin. J Neural Transm Suppl, 2002(62): p. 277-85.

16. Ruether, E., et al., A 28-week, double-blind, placebo-controlled study with Cerebrolysin in patients with mild to moderate Alzheimer's disease. Int Clin Psychopharmacol, 2001. 16(5): p. 253-63.

17. Chen, N., et al., Cerebrolysin for vascular dementia. Cochrane Database Syst Rev, 2013. 1: p. CD008900.

18. Gavrilova, S.I., et al., [ApoE genotype and efficacy of neurotrophic and cholinergic therapy in Alzheimer's disease]. Zh Nevrol Psikhiatr Im S S Korsakova, 2005. 105(4): p. 27-34.

19. Alvarez, X.A., et al., A 24-week, double-blind, placebo-controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimer's disease. Eur J Neurol, 2006. 13(1): p. 43-54.

20. Alvarez, X.A., et al., Combination treatment in Alzheimer's disease: results of a randomized, controlled trial with cerebrolysin and donepezil. Curr Alzheimer Res, 2011. 8(5): p. 583-91.

21. Thome, J. and E. Doppler, Safety profile of Cerebrolysin: clinical experience from dementia and stroke trials. Drugs Today (Barc), 2012. 48 Suppl A: p. 63-9.

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