Khavinson Vladimir Kh
Saint Petersburg Institute of Bioregulation and Gerontology, 3 Dinamo Pr, Saint Petersburg, 197110, Russia.
Neuro Endocrinol Lett. 2002;23 Suppl 3:11-144.
A technology has been developed for manufacturing of biologically active complex peptide preparations from extracts of different tissues. In particular, the pineal preparation (Epithalamin) augments the in vitro outgrowth of explants from the pineal gland but not from other tissues, the latter being stimulated by peptide preparations from respective tissues. Epithalamin increases melatonin production by the pineal gland of rats, improves immunological parameters in rats and mice, produces anticarcinogenic effects in different experimental models, stimulates antioxidant defenses, and restores the reproductive function in old rats. These effects are combined in the ability of Epithalamin to increase the lifespan in rats, mice, and fruit flies. Many of these effects are reproduced in clinical trials, which have demonstrated the geroprotector activity of Epithalamin in humans. Among the effects of the thymic preparation Thymalin, those related to its ability to stimulate immunity are the most prominent. This ability is associated with anticarcinogenic and geroprotector activities. Clinical trials of the peptide preparations obtained from other organs including the prostate, the cerebral cortex, and the eye retina, have demonstrated beneficial effects reflected by the improvement of the conditions of respective organs. Based on the data about the amino acid compositions of the peptide preparations, novel principles of the design of biologically active short peptides possessing tissue-specific activities has been developed. Dipeptides specific for the thymus and tetrapeptides specific for the heart, liver, brain cortex, and pineal glands stimulate the in vitro outgrowth of explants of respective organs. Interestingly, for eye retina and the pineal gland, a common tetrapeptide Ala-Glu-Asp-Gly (Epitalon) has been designed, probably reflecting the common embryonal origin of these two organs. Epitalon reproduces the effects of Epithalamin including those related to its geroprotector activity. In particular, Epitalon increases the lifespan of mice and fruit flies and restores the circadian rhythms of melatonin and cortisol production in old rhesus monkeys. At the same time, Epitalon prolongs the functional integrity of the eye retina in Campbell rats with hereditary Retinitis Pigmentosa and improves the visual functions in patients with pigmental retinal degeneration. Changes in gene expression were observed to be produced by the short peptide preparations. Therefore, the effects of Epitalon are suggested to be mediated by transcriptional machinery common for the pineal gland and the retina and, probably, for regulation of melatonin production in fruit flies. Based on three decades of studies of the peptide preparations, the peptide theory of ageing has been put forward. According this theory, ageing is an evolutionary determined biological process of changes in gene expression resulting in impaired synthesis of regulatory and tissue-specific peptides in organs and tissues, which provokes their structural and functional changes and the development of diseases. Correspondingly, correction of such disorders by means of stimulation of peptide production in the organism or through their delivery can promote the normalisation of disturbed body functions.
已开发出一种从不同组织提取物中制造生物活性复合肽制剂的技术。特别是，松果体制剂（Epithalamin）可促进松果体外植体在体外的生长，但不能促进其他组织外植体的生长，而后者可被来自相应组织的肽制剂刺激。Epithalamin可增加大鼠松果体的褪黑素分泌，改善大鼠和小鼠的免疫参数，在不同实验模型中产生抗癌作用，刺激抗氧化防御，并恢复老年大鼠的生殖功能。这些作用共同体现为Epithalamin可延长大鼠、小鼠和果蝇的寿命。这些作用中的许多在临床试验中得到重现，这些试验已证明Epithalamin在人类中的老年保护活性。胸腺制剂胸腺素（Thymalin）的作用中，与其刺激免疫能力相关的作用最为突出。这种能力与抗癌和老年保护活性相关。从包括前列腺、大脑皮层和视网膜等其他器官获得的肽制剂的临床试验已证明，相应器官状况的改善反映出有益效果。基于关于肽制剂氨基酸组成的数据，已开发出设计具有组织特异性活性的生物活性短肽的新原理。对胸腺特异的二肽以及对心脏、肝脏、大脑皮层和松果体特异的四肽可刺激相应器官外植体在体外的生长。有趣的是，针对视网膜和松果体，设计出了一种共同的四肽Ala-Glu-Asp-Gly（Epitalon），这可能反映了这两个器官共同的胚胎起源。Epitalon重现了Epithalamin的作用，包括与其老年保护活性相关的作用。特别是，Epitalon可延长小鼠和果蝇的寿命，并恢复老年恒河猴褪黑素和皮质醇分泌的昼夜节律。同时，Epitalon可延长患有遗传性视网膜色素变性的坎贝尔大鼠视网膜的功能完整性，并改善色素性视网膜变性患者的视觉功能。观察到短肽制剂可引起基因表达的变化。因此，推测Epitalon的作用是由松果体和视网膜共有的转录机制介导的，可能也参与果蝇褪黑素分泌的调节。基于对肽制剂三十年的研究，提出了衰老的肽理论。根据这一理论，衰老是一种进化决定的生物过程，基因表达发生变化，导致器官和组织中调节肽和组织特异性肽的合成受损，从而引发其结构和功能变化以及疾病的发展。相应地，通过刺激机体中肽的产生或通过其递送来纠正此类紊乱，可促进紊乱的身体功能正常化。
