Cortexin® for children

This term is frequently met in medical publications, mass media, pharmaceutical advertising. Neuroprotection opportunities are rooted in the nature of the brain, in genes and regulatory neuropeptides. The essence of neuroprotection is that treatment both protects the affected group of neurons and ensures its further functioning. Is there an adequate pharmacological interaction that can launch the natural mechanisms and support them at the needed level? The question is important for medicine. In this regard, searching, creation and testing of new pharmaceutical agents are and will be one of the most crucial trends in modern pharmacology.

Searching new neuroprotectors is a complex process that requires combined effort of doctors, biologists and pharmacologists at all the stages. Peptides need special attention here. In spite of their diversity, they are knit together by a number of common characteristics such as low dosage, no pronounced toxic effects, mild and long-term duration. Cumulatively, it can be asserted that a system of peptides in the body (S. V. Koroleva, I. P. Ashmarin, 2006) formed during million years of evolution regulates all functions at many levels including processes ultimately leading to the neuroprotective effect. In the informational aspect, peptides represent a universal language which is clear and natural for living organisms both at the systemic, and cellular levels.

Cortexin®, a drug with proven clinical, biological, cellular, genetic and molecular effectiveness, is an example of successful development based on the abovementioned principles.

According to MRI data, there is a lesion in the right temporal area of the brain. Its volume is increased by day 3. In such a lesion, a glial scar and poststroke cysts are formed by day 28. When a patient with ischemic stroke takes Cortexin from the first hours of the disease, significant improvement of general health, clinical and neurological pictures are observed and the volume of brain lesion is decreased by 40 % by day 28. This is a bright example of a neuroprotective effect of Cortexin (A. A. Skomoretz, V. I. Skvortsova, 2008).

Terms: Ischemia is insufficient blood supply of any organ or part of tissue due to blockage or narrowing of the respective artery; ATP, adenosine triphosphate, is a vital nucleotide and the body's most important energy-transfer molecule; the compound is known as a universal source of energy for all biochemical processes occurring in living systems. Depolarization of the cell membrane is a change of the electrical potential on a cell membrane; glutamate is an amino acid, basic excitatory neurotransmitter. Binding of glutamate to neuronal specific receptors results in neuron excitation. The activation of neurons causes the release of glutamate, which then binds to NMDA- and AMPA-glutamate receptors. Caspases, NO-syntases are intracellular enzymes involved in cell death and oxidative stress.

Neuroprotective anti-apoptotic effect

Cortexin® is a neuroprotective agent with a therapeutic effect within the first hours following an ischemic cerebral lesion. It means that its main target is the area of penumbra, i.e. the area surrounding an ischemic event with reduced transport of oxygen and energy but still viable for up to 6 hours. Subsequent restoration of nerve functions, a patient’s life and death depend on the process outcome. Cortexin® produces an effect on all links of the pathological chain of molecular events leading to neuronal death. It has been shown that Cortexin® reduces neuronal apoptosis (programmed cell death) due to glutamate excessive accumulation (Pinelis et al., 2008).

Glutamate is the primary excitatory neurotransmitter of the central nervous system. In a stroke, excessive release of glutamate launches a cascade of processes resulting in neuronal death. Entry of glutamate in nerve tissue culture also kills neurons. If glutamate is accompanied by a neuroprotective agent, less neurons die. Results obtained in the study of Cortexin® neuroprotective properties in vitro are presented in this figure: in concomitant administration with glutamate, Cortexin® produces a pronounced neuroprotective effect in the nanogram range (*p < 0.05 as compared to control group) (O. K. Granstrem et al., 2008).

Restoration of ATP synthesis

Adenosine triphosphate (ATP) is a nucleotide which is extremely important in energy exchange and metabolism and which is a universal source of energy for all cells. Drop of ATP levels in cerebral cells is a central link of all pathological processes against the background of cerebral ischemia. Decreased synthesis and increased expenditure of ATP are developed soon after initiated ischemia of the nerve tissue (Sorokina et al., 2007). It has been shown in recent studies that Cortexin® can restore the levels of ATP in neurons.

According to the study, Cortexin® is able to initiate the processes of natural regeneration of ATP in the mitochondria of nerve cells. Due to the fact that the fall in the ATP level is one of the main causes leading to the death of neurons in stroke, recovery of this parameter under the influence of Cortexin® explains its clinical efficacy (O. K. Granstrem et al, 2008).

Delayed calcic disregulation (DCD) depression

In cerebral ischemia and stroke an increased penetration of calcium ions into neurons is observed; it results in an irreversible increase in intracellular calcium concentration and the subsequent malfunction of the mitochondria. This is associated with a fall in a mitochondrial potential (ΔΨm) (Khodorov et al, 2001; Krieger C. & Duchen M. R., 2002). As a rule, the cells with a collapse of ΔΨm after a decrease in glutamate, do not restore the initial potential and, eventually, die. This is so-called delayed calcium disregulation (DCD) phenomenon (De Wied D., 1997; E. G. Sorokina et al., 2007).

Studies of the mitochondrial potential (ΔΨm) by fluorescence microscopy demonstrate that Cortexin significantly slows down the development of calcium deregulation during glutamate action. The recorded mitochondrial potentials of the neurons presented in the figure show a protective effect of Cortexin® due to the delay in the onset of calcium disregulation. Thus, this figure demonstrates that the use of Cortexin® can extend the therapeutic window when there is an ischemic lesion in nervous tissue (Report on the Study of the neuroprotective effect of Cortexin®, SI Children Health Science Center, RAMS, Moscow, 2008).

Neurotrophic effect

Peptides of Cortexin® have a direct and indirect neurotrophic effect on the cells. The basic mechanisms of this effect are based on the changes in gene expression of neurotrophic factors such as a brain-derived neurotrophic factor (BDNF) and a nerve growth factor (NGF).

Stimulation of neurite growth in the chick embryo brain culture. In the nerve tissue culture the growth of neurites (nerve cell processes through which nerve impulses run from the cell body to the organs and other nerve cells) occurs only in the presence of neurotrophic factors. In this experiment, the addition of Cortexin® allows for the determination of the degree of its neurotrophic effect. On the right photograph the entire field around the island of a nervous tissue is occupied by an extensive neurite network, whereas, in the control group (left photograph) the growth of neuronal processes are few in number. There are results of the drug series testing in the photos. Such testing is regularly carried out in the analytical laboratory of GEROPHARM LLC.

Thus, numerous independent studies convincingly demonstrate that Cortexin® has multiple effects which regulate a cascade of proteins involved in apoptosis, expression of neurotrophic factors, energy supply to the nerve cells, mitochondrial potential, functioning of glutamate receptors and regulation of calcium ion concentration in the cell. This, as a whole provides a neuroprotective and neurotrophic effects of the drug, and, as a result, a high treatment efficiency and improvement in the patient’s quality of life.

Certain results obtained by Russian medicine when using Cortexin® in clinical practice are shown in detail in section Scientific Publications

References:

1. Gerasimova M. M., Petushkov A. Yu. / Cortexin effect on the cytokine metabolism in lumbosacral radiculopathies. Neuroimmunology – 2004. – Vol. II. – No. 2. – p. 26.
2. Granstrem O. K., Sorokina E. G., Storozhevykh T. P., Stuchnaya G. V., Pinelis V. G., Dyakonov M. M. / The latest news on Cortexin (neuroprotection at the molecular level). Terra Medica Nova. – No. 5. – 2008. – pp. 40–44.
3. Koroleva S. V., Ashmarin I. P. / Development and Application of the Expert System for Analysis of the Functional Continuum of Regulatory Peptide // Bioorganic Chemistry. – 2006. – Vol. 32. – No. 3 – pp. 249–257.
4. Skoromets A. A., Stakhovskaya L. V., Belkin A. A., Shekhovtsova K. V., Kerbikov O. B., Burenchev D. V., Gavrilova O. V., Skvortsova V. I. / New Possibilities in Neuroprotection in the Treatment of Ischemic Stroke // Journal of Neurology and Psychiatry named after S. S. Korsakova. 2008. – Vol. 22. – pp. 32–38.
5. Sorokina E. G., Reutov V. P., Senilova Ya. E., Khodorov B. I., Pinelis V. G. / Change in ATP Content in Cerebellar Granule Cells During Hyperstimulation of Glutamate Receptors: Possible Involvement of NO and Nitrite Ions // Bull. Experimental. biol. and med. – 2007. – No. 4. – pp. 419–422.
6. Khodorov B. I., Storozhevykh T. P., Surin A. M., Sorokina E. G., Yuravichus A. I., Borodin A. V., Vinskaya N. P., Khaspekov L. G., Pinelis V. G. / Mitochondrial depolarization plays a dominant role in the mechanism of disturbance of neuronal calcium homeostasis induced by glutamate // Biol. membranes. – 2001. – Vol. 18, No. 6. – pp. 421–432.
7. De Wied D. / Neuropeptides in learning and memory processes. // Behav. Brain. Res. – 1997. – Vol. 83. – pp. 83–90.
8. Krieger C. and Duchen MR. / Mitochondria, Ca2+ and neurodegenerative disease. // Eur. J. Pharmacol. – 2002. – Vol. 447. – pp. 177–188.
9. O’Collins V. E., Macleod M. R., Donnan G. A., Horky L. L., van der Worp B. H., and Howells D. W. “1,026 Experimental Treatments in Acute Stroke” // Annals of Neurology. – 2006. – 59:467–477.
10. Pinelis V. G., Storozhevykh T. P., Surin A. M., Senilova Ya. E., Persiyantzeva N. F., Tukhmatova G. R., Andreeva L. A., Myasoedov N. F., Granstrem O. “Neuroprotective effects of cortagen, cortexin and semax on glutamate neurotoxicity” / 30th European Peptide Symposium (30EPS), Helsinki, 30 August – 5 September 2008.