Since1973, V.Kh. Khavinson and his collaborators have isolated from tissues of mammals more than 20 physiologically active substances, comprised mainly of 1 to 10 kDa peptides. Five of them, i.e. Cortexin derived from the brain cortex, Eipthalamin from the pineal gland, Prostatilen from the prostate, and Retinalamin from eye retina, are licensed for medical applications and included in the State Pharmacopoeia of the Russian Federation.
In 1985, V.G. Morozov and V.Kh. Khavinson have put forward the hypothesis that peptides comprised by such preparations are involved in gene regulation. The hypothesis was then confirmed by numerous studies.
The ability of some peptide preparations to increase lifespan in animal models and to retard the development of cancer and atherosclerosis, which are the main causes of premature death in humans, makes reasons to regard them as geroprotectors. The main benefit of these peptide complexes is that they are not toxic and cannot be overdosed in principle.
Increases in lifespan
Thymalin and Epithalamin administration to rats was associated with significant, by 25-40%, increases in their lifespan compared with controls.
Impacts on carcinogenesis
Peptides derived from the pineal gland and thymus showed robust antitumour activity manifested as 1.4- to 7.0-fold decreases in the frequencies of occurrence of spontaneous and radiation- and substance-induced malignancies in animals.
Unprecedented decreases in tumour incidences were observed in most experiments. With account of the common mechanisms of carcinogenesis in all mammals, these results deserve being regarded as immensely important for preventing cancer in humans.
Cortexin® is a peptide complex derived from cattle and hog brain cortex and possessing a pronounced neuroprotector activity. Cortexin stimulates reparatory processes in the brain and accelerates the rehabilitation of brain function after stresses.
Cortexin administration (10 mg i.m. daily for 10 days) to patients with organic emotionally labile (asthenic) disorder (ICD-10, F06.6) was associated with decreased blood cortisol levels. In patients whose ongoing therapy was supplemented with Cortexin, blood thyroid hormones and thyrotropin were normalized.
Cortexin is used to treat cerebrovascular disorders, asthenic conditions and encephalopathies of different origins in advanced-age patients.
The targets of Cortexin are neuronal and glial cells. In injured brain, Cortexin influences the key steps of processes culminating in neuron death: inhibits apoptosis caused by excessive liberation of glutamate into synaptic clefts and thus attenuates the hyperstimulation of glutamate receptors.
Cortexin may be useful for patients with cranial trauma, cerebrovascular disorders, viral and bacterial neuroinfections, encephalopathies of different etiologies, and acute and chronic encephalitis and encephalomyelitis. Cortexin administration (10 mg i. m. daily for 10 days) to 58 elderly and old patients having organic mental disorders helped to restore their cognitive functions, such as memory and intellection, and immunological parameters. Repeated treatment courses were associated with more pronounced and prolonged effects.
When complex therapy for cranial trauma in 174 patients was supplemented with Cortexin at the above dose regimens, this helped to normalize the parameters of EEG and transcranial ultrasound dopplerography.
According to evidence obtained in a multicenter randomized prospective double-blind trial of Cortexin, this preparation proved to be effective in treating acute ischemic stroke in 272 patients aged 30 to 80 years. Cortexin at the dose of 10 mg i.m. was administered twice daily for 10 days, and the treatment course was repeated in 10 days. The following findings were reported: (a) the restoration of neurological functions assessed by the NIH, Rankin and Rivermead Scales and (b) the amelioration of cognitive disorders (MMSE Scale) and motor deficits (Barthel index of activities in daily living). These effects persisted for about one month after the completion of the second treatment course.
Cortexin has been found to be effective in patients with chronic cerebrovascular diseases. The preparation was administered at 10 mg twice daily for 14 days to 31 Stages I-II dyscirculatory encephalopathy patients aged 50 to 75 years. Life quality was improved in 97% of the patients. In 90% of the cases, the patients reported the attenuation of their subjective symptoms, such as emotional instability, fatigue, headache, and vertigo. An amelioration of vestibulo-cerebellar and vegetative symptoms was noted. Auditory and speech memory improved. The amplitude of cognitive evoked potential increased, and their latency decreased. The diminution of activity zones in the temporal and frontal brain areas according to IMR data suggests that the energy cost of responding to standard psychological tests was reduced.
The neuroprotector effects of Cortexin are based on its ability to enhance serotonin and gamma-aminobutyric acid (GABA) production. Cortexin was found to stimulate dopamine liberation from axons of striatal neurons and, at the same time, to suppress dopamine action on pre- and postsynaptic receptors. The neuroprotector properties of Cortexin are also associated with its ability to inhibit apoptosis and stimulate neuron proliferation.
In cultured neurons from the cerebellum, cortex and hippocampus, Cortexin retards the development of delayed calcium deregulation caused by glutamate. In organotypic cultures of chick embryo brain, Cortexin stimulates neurite outgrowth.
It has been suggested that the activation of neuronal cell renewal by Cortexin is associated with changes in the expression of genes that regulate the synthesis of cell's own neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF).
Cortexin delivered in two 10-day courses is effective in the treatment and rehabilitation of patients during acute and early restorative periods of ischemic stroke. Cortexin effectiveness is especially high in elderly and old patients.
Anticancer effects of Cortexin have been noted. In a rat model of transplacental nitrosourea-induced carcinogenesis, tumours of the brain, spine, peripheral nervous system, and kidney develop. Cortexin treatment was associated with reduced tumour incidence and multiplicity, probably because of Cortexin ability to normalize glial cell differentiation and proliferation .
The use of Cortexin alone or in combination with Retinalamin renders pronounced protective effects in diabetic retinopathy, macular dystrophy, optic nerve atrophy, glaucoma and other eye diseases [28, 99]. In patients who have undergone not less than two annual courses of Cortexin treatment over 7-10 years, visual acuity was 2.5 times better than in patients who received conventional therapies.
Cortexin is effective in virtually healthy subjects under extreme environmental and occupational conditions or upon over-fatigue or asthenia. The preparation enhances short-term and long-term memory, accelerates information processing, mental reactions, and spatial coordination, and facilitates attention focusing and the adequacy of perception. Cortexin is also able to improve mood, to enhance vital activity, and to reduce anxiety and mental stress. Epithalamin, too, may be used to control pathological conditions associated with increased intellectual and psycho-emotional efforts, elderly patients included.
In 58 elderly patients aged 60 to 74 years who suffered from hypertension-associated angioretinopathy, Cortexin improved vision acuity, which even three months after therapy remained 20% higher than before it. Doppler angiography clearly showed that microcirculation was improved in the patients.
Thymalin® was isolated from calf thymus. The preparation contains more than 10 peptide components. Among amino acids, Glu, Asp, Gly and Lys are the most prevalent.
Thymalin proved to be effective in treating a number of conditions associated with reduced cellular immunity and phagocytosis, including complications of radiotherapy and chemotherapy in cancer patients, acute and chronic infections and inflammatory conditions, complications of massive doses of antibiotics, sluggish tissue regeneration upon posttraumatic and post-operation complications, obliterating diseases of limb arteries, and chronic diseases of the liver and prostate, and in complex therapy for certain forms of tuberculosis and leprosy.
Thymus, the central of the immune system, undergoes involution in the course of ageing. This process is associated with decreases in the production of peptide regulators by the thymus.
In experimental settings, Thymalin was administered to mice treated in utero with N-nitroso-N-ethylurea. Thymalin administration started from 2.5 months postpartum and continued for the rest of animal's life. The treatment was associated with a 1.5- to 2.5-month increase in the latent period of tumour development. The prevalence of spine tumours decreased by about 30%. Thus, Thymalin produced a clear inhibitory effect on transplacental N-nitroso-N-ethylurea-induced carcinogenesis.
In SHR mice treated with Thymalin starting from the fourth month of life, the prevalence of spontaneous tumours decreased from 55 to 44%. In CH3/Sn female mice treated lifelong with Thymalin starting from 1 month of age, the prevalence of spontaneous tumours, including mammary adenocarcinoma, decreased 2.8-fold and 2.6-fold, respectively.
This peptide preparation has been shown to regulate metabolic processes in the retina, to render pronounced protective effects on the vascular endothelium and on the collagen fibres of perivascular connective tissues, and to enhance the repair of damaged structures of the vascular wall. Retinalamin induces differentiation as suggested by its ability to induce the development of retinal cells and pigmented epithelium upon addition to the pluripotent cells of the ectoderm of the early gastrula of the frog Xenopus laevis.
In Campbell rats having hereditary pigmented degeneration of the retina, Retinalamin inhibited dystrophic processes.
The twenty years-long experience of the use of Retinalamine in treating eye diseases of different origins proved that this preparation is highly effective clinically. Retinalamin has been found to enhance functional interactions between pigmented epithelium and the outer segments of photoreceptor cells, metabolic regulation, antioxidant defence activation, and retina sensitivity to light. Many years of application of Retinalamin in treating pigmented retinitis patients showed that the preparation is highly potent being able to provide for beneficial clinical results in 90% of cases. After treatment with Retinalamin as parabulbar injections at daily doses of 5 to 10 mg for 10 days, central scotomas reduced in size or disappeared in all of 250 patients having advanced age-associated macular degeneration and retinal pigmented epithelium atrophy. The use of Retinalamin was associated with a significant enhancement of vision (vision acuity improvement and vision field expansion) and related electrophysiological parameters and with the improvement of somatic conditions and blood antiradical defenses in all patients (Tables 3 and 4). The use of Retinalamin for treating pigmented retinitis was found to produce no adverse side effects, complications, or drug dependence, even in patients having unfavourable allergological anamneses.
A peptide preparation derived from animal prostate, proved to be effective in therapy for chronic prostatitis, benign prostatic hyperplasia, complication of surgery on the prostate, and various age-associated dysfunctions of the prostate.
Among all peptide preparations derived from animal tissues, only Prostatilen was found to stimulate the growth of rat prostate and bladder explants.
Prostatilen notably increases the efficiency of treatment of age-associated prostate diseases and, by influencing male sexual functions, significantly prolongs male sexual activity.
A peptide preparation derived from bovine pineal gland, was used to treat elderly patients showing accelerated ageing of their cardiovascular system. In a randomized comparative study, a decrease in the rate of ageing and in mortality over 15 years of follow-up was found. The long-term use of Epithalamin (6 treatment courses during 3 years) has been found to decrease the rate of ageing of the cardiovascular system, to restore physical performance reduced because of ageing, and to normalize carbohydrate and lipid metabolism and the diurnal rhythm of melatonin secretion. The geroprotector activity of Epithalamin is also manifested in reduced mortality as suggested by the analysis of Kaplan-Meier survival plots.
Ageing is associated with lymphopenia and impaired blast transformation of T-cells; however, in old female C3H/Sn mice treated daily with Epithalamin starting from the age of 3.5 months, phytohemagglutinin-induced T-cell blast transformation was the same as in young mice.
Epithalamin has been shown to reduce lipid peroxidation as follows from a 4.1-fold decrease in diene conjugate level, suggesting that the early stages of lipid peroxidation are inhibited. Superoxide dismutase activity was reported to increase in rat blood one week after the onset of Epithalamin administration.
Epithalamin is weakly cytostatic towards sarcoma-37 cells in vitro.
In vivo, Epithalamin administration to female rats starting from 15 months of age reduced the incidence of all tumours and malignant tumours 1.6 fold and 2.7 fold, respectively.
Epithalamin markedly enhanced the cytostatic effect of laser irradiation of tumours, as assessed by the number of tumour foci, and attenuated the metastasizing of Pliss lymphosarcoma and lung carcinoma in rats.
In mice, Epithalamin produced anti-tumour effects on transplantable tumours, including mammary cancer, squamous cell cervical carcinoma, 22a hepatoma, and LIO-1 lympholeukemia, but had no effect on Harding-Passey melanoma and L-1210 leukemia.
Epithalamin has been shown to decrease the incidence of DMBA-induced mammary adenocarcinomas in rats. It was suggested that the antitumour effect of Epithalamin might be manifested under the conditions of cancrophilia syndrome induced by tumour transplantation or by chemical carcinogens.
Significant antitumour effects are produced by the combined use of peptide preparations derived from the pineal gland and thymus. Their concerted action is manifested in 1.4- to 7.0-fold decreases in the incidences of malignant tumours, either spontaneous or induced with irradiation of chemical carcinogens. Such decreases were reported in a vast majority of experiments.
Daily administration of 0.5 mg Epithalamin prolonged the lifespan of rats by 25%.
In C3H/Sn mice, daily administration of Epithalamin starting from the age of 3.5 months increased the mean and maximal lifespan by 40% and 25% (by 3.5 months) respectively.
Epithalamin and Thymalin significantly increased the lifespans of drosophila flies and mice and rats by 25-40% compared with controls. In a number of experiments, the maximal lifespan was also shown to increase to some extent.
Epithalamin effects on the endocrine regulation were studied in rabbits. It was shown that Epithalamin administration for three weeks was associated with decreased blood insulin and triglyceride levels and increased glucose tolerance. Intraperitoneal Epithalamin administration to rats was associated with a significant increase in blood cortisol.
Epithalamin effects on the reproductive function in old rats with persistent estrus were manifested in the restoration of regular estrous cycles. In old female rats, Epithalamin reduced blood luteinizing hormone and prolactin, elevated blood triiodothyronine and increased hypothalamo-pituitary system sensitivity to the homeostatic inhibition of the corticotrotin secretion by glucocorticoids. In young male rats, increases in blood triiodothyronine and decreases in blood thyroxin were observed upon Epithalamin administration for five days.
Of special importance is the ability of the peptide preparation derived from the pineal gland to restore the reproductive function in old female rats.
In 57 women with dyshormonal vegetative myocardiodystrophy who received i.m. injections of 10 mg Epithalamin daily for 5-10 days in 4-6 months intervals, their general conditions and ECG were improved after the first injection, and this effect persisted over the entire follow-up period. Other changes included significant decreases in blood follicle-stimulating hormone levels and the improvement of electrolyte balance.
Women with dysovarian vegetative myocardiodystrophy received 10 mg i.m. Epithalamin daily for 10 days. In 68% of the patients, blood gonadotropins and estradiol levels were normalized, the rates of cardiovascular disorders decreased 3.2-fold, and the repolarization phase of ECG was restored.
In ten patients with aspirin asthma in remission or in the course of subsiding exacerbation, antiasthma therapy with glucocorticoids was supplemented with i.m. Epithalamin at a 10-mg daily dose for 10 days. Twelve control patients received glucocorticoids and i.m. water injections. By the end of the treatments, most patients showed decreased daytime frequencies of asthmatic symptoms and improved tolerance to physical stresses, strong odours, and cold air. Pulmonary wheezes subsided or disappeared. Responses to Berotec N at the level of distant bronchi improved by 52%. In 40% of the patients by the end of the treatment and in 90% in ten days after the end, the excretion of 6-oxymelatonin sulfate (the main metabolite of melatonin) with urine increased by 68%, and the parameters of cellular and humoral immunity improved, which altogether suggests that the initially reduced melatonin production increased. The use of Epithalamin made it possible to reduce the dosages of antiasthmatic drug inhalation for up to 6 months. No acute respiratory diseases in the patients were reported during all this time.