Pharmacology: Cerebrolysin is a nootropic drug with proven neurotrophic action. Cerebrolysin is brain-specific; it acts specifically inside neurons and affects the central nervous system in a multimodal way. The effects of Cerebrolysin are results of the interaction of its peptides; the low molecular-weight peptides pass through the blood-brain barrier to produce effect on neurons and are biologically active substances of Cerebrolysin. The early in vitro experiments of Cerebrolysin research were done and the effects of 3 different solutions (Cerebrolysin, a peptide-enriched Cerebrolysin (E021), a synthetic amino acid solution which corresponds to the amino acid fraction of Cerebrolysin on the oxygen consumption of homogenous rat brain) proved that the peptide-enriched Cerebrolysin has a major effect.
The multimodal actions of peptides in Cerebrolysin are as follows: Neurotrophic stimulation like natural neurotrophic factors [eg, nerve growth factor (NGF)]; neuromodulation; and metabolic regulation.
Neurotrophic Stimulation: The peptides have unique neurotrophic effects. These secure the survival, differentiation and protection of nerve cells. Cerebrolysin has proven neurotrophic action. Its action has been proven both in vitro and in vivo.
The survival and differentiation of cultured nerve cells both produced by Nerve Growth Factor (NGF) and Cerebrolysin (neurite outgrowth) were observed but not in a control group nor group of cultured nerve cells receiving other compounds. The morphological difference in clumps of neurons and outgrowth nerve fibers and the difference in the beginning of outgrowth nerve fiber revealed in comparison with NGF, showed that Cerebrolysin did not consist of NGF and might have a different mechanism in its effects on the neuron from NGF. In vivo, the neurotrophic factor-like effect of Cerebrolysin has been demonstrated in a study of fimbria fornix transaction in the rat brain. Cerebrolysin promoted the survival of up to 20% of septal cholinergic neurons in the rat brain after intraperitoneal injection. The antidegeneration effect of Cerebrolysin on septal cholinergic neurons after fimbria fornix transaction has been demonstrated (its neurotrophic effect has been known as the antidegeneration effect of NGF on septal cholinergic neurons after fimbria fornix transaction in the rat brain).
Neuromodulation: Improvements of behavior, memory and learning are results of modulating the synaptic plasticity of neurons. Cerebrolysin's effects on neuromodulation have been demonstrated in experiments. It can inhibit synaptic transmission in the CA1 area of the hippocampus (specific area of brain responsible for higher functions) via GABAβ-receptor. It acts preferentially on presynaptic GABAβ-receptor and has no detectable postsynaptic inhibitory effects. The inhibition of excitatory synaptic transmission in CA1 area of the hippocampus via activation of GABAβ-receptor decreases Ca2+-influx through voltage-dependent Ca2+-channels. The therapeutic effect of Cerebrolysin on hypoxia, ischemia and brain injuries could be explained clearly since previous studies have been published.
Another investigation, which leads to the understanding of Cerebrolysin's mechanism was the investigation on presynaptic of adenosine A1-receptor in the rat hippocampus. Cerebrolysin produces the release of endogenous adenosine, which is a potent inhibitor of glutamatergic synaptic transmission; Cerebrolysin acts as neuroprotective agent.
The neuromodulation of Cerebrolysin is a result of modulating synaptic plasticity and can improve behavior, memory and learning capacity.
Metabolic Regulation: Cerebrolysin can regulate metabolic disturbances and can normalize metabolic disorder inside neurons.
Experimental studies on brain slices and homogenates revealed an improvement of aerobic energy metabolism with Cerebrolysin.
Cerebrolysin significantly lowers lactate concentration in the brain at almost normal level; this key action resulted in reduced formation of free oxygen radicals.
In protein synthesis, Cerebrolysin increases leucine incorporation in neurons after in vivo application thus increasing the rate of protein synthesis. Histological studies showed Cerebrolysin enhanced number of polysomes in neurons, increased number of membrane-bound ribosomes and polysomes. This high ratio of membrane-bound ribosome, respectively polysomes to monosomes, points to an enhanced protein synthesis.
With all the mechanism of action, Cerebrolysin secures nerve cell, prevents cytotoxicity, induces neuronal differentiation, guarantees full neuronal function and protects different types of ischemic and neurotoxic lesions.
Effects of Cerebrolysin in patients suffering from dementia (including Alzheimer's disease), stroke, craniocerebral injuries have been demonstrated in clinical trials according to GCP (Good Clinical Practice).
In controlled clinical trials, Cerebrolysin leads to an improvement in the cognitive performance and mood of patients suffering from Alzheimer's disease. In these patients, marked improvement is observed in 61.7% of the Cerebrolysin-treated group [assessed by CGI scale (Clinical Global Impression scale) and SCAG scale (Sandoz Clinical Assessment of Geriatric)].
Quantitative EEG studies of healthy volunteers and patients suffering from vascular dementia have shown dose-dependent acute effects of elevated neuronal activity (increased α/β frequencies) after 4 weeks of treatment.
With stroke patients, Cerebrolysin as add-on therapy improves significantly the outcome after 4 weeks of therapy. The improvements also have been observed in neuroimaging procedures as CT scanner, MRI and SPECT. Cerebrolysin's action in stroke is on the nerve cells of penumbra zone by regulating metabolism and normalizing the disturbances of the neurons.
In craniocerebral trauma, Cerebrolysin reduces the cytotoxic edema of the neurons. It acts as a neuroprotector and leads to an accelerated recovery and reduction of sequela.
Pharmacokinetics: Cerebrolysin is a highly complex peptide preparation with a unique neurotrophic activity. It is impossible to follow the distribution and metabolism of all of Cerebrolysin's peptides in the human body because of interactions and enzymatic resistance. Therefore, its pharmacokinetics is functional pharmacokinetics, demonstrated by its neurotrophic effect and influence on brain activities in humans.
Neurotrophic effect of the peptides is dose-dependent. Up to 8 hrs after an IV administration of Cerebrolysin, neurotrophic activity can be detected in the human serum, indicating long-lasting effects, even after a single IV administration. In a follow-up study of the clinical trials, the effects of Cerebrolysin can be seen after stopping treatment up to 6 months, which proved long-term effects of Cerebrolysin's neurotrophic activity.
Cerebrolysin's peptides pass through the blood-brain barrier, which is demonstrated by pharmacokinetic investigation and the comparisons of intracerebrally and peripherally administered Cerebrolysin.
In contrast to the natural Nerve Growth Factor, Cerebrolysin's peptides save medial septal cholinergic neurons in CA1 region of hippocampus after peripheral application.
Cerebrolysin modulates the molecular composition of the blood-brain barrier. It affects the expression pattern of glucose transporter GLUT1 in cultured brain capillary endothelial cells by increasing the stability of GLUT1 mRNA transcript and inducing a new steady-state level of these carriers.
Toxicology: Cerebrolysin is generally well tolerated and possesses an extremely high margin of safety. In human therapeutic dosage, Cerebrolysin produces almost no toxic symptoms. The toxicological data are listed as follows: Acute Toxicity: After single IV administration of Cerebrolysin, the following LD50 values were observed (observation period: 14 days): Male rats 68 mL/kg body weight; female rats 74 mL/kg body weight; dogs: Male and female >52.2 mL/kg body weight.
Chronic Toxicity (Multiple doses >6 months): Rat received up to 12.5 mL/kg body weight daily for 26 weeks: Only moderate changes in blood count were observed; dog: The highest administered doses were 9 mL/kg body weight daily for 26 weeks (about 10 times the human therapeutic dosage) and 4.5 mL/kg body weight for 26 weeks (about 5 times the human therapeutic dosage): No systemic substance-dependent intolerance reactions were observed.
Reproductive Toxicity: Cerebrolysin was injected IV to the dams at the highest possible volumes; in no case was an alteration of gestagenic period was observed, neither in rats nor in rabbits. Neither embryotoxic nor teratogenic effects nor impairments of embryonic or neonatal developments were found; no influence on the progenic (F1, F2 generation) was evident. No influence on fertility and the reproductive performance of the parent animals was observed.
Mutagenicity, Sensitising Effect and Carcinogenicity: Cerebrolysin does not show any mutagenic potential, sensitizing effect or carcinogenicity in toxicological tests neither in vitro nor in vivo.
Sensitising Potential: Larger molecular weight peptides with antigenic potential are excluded from the infusion solution due to the manufacturing and quality control processes. The result of immunological testing shows no influence on the immune system. These tests revealed that Cerebrolysin does not result in the formation of antibodies or cutaneous anaphylaxis. Cerebrolysin shows no histamine-stimulating potential and no hemagglutinating effects.
In humans, the safety data have been collected for many years. Over the past 30 years of use, Cerebrolysin has been shown no indication that any form of infectious animal substrate is transmissible. In 1994, the German Ministry of Health confirmed the harmlessness of Cerebrolysin in respect to mad cow disease and the general safety requirements for medicaments of animal origin.