The neuroprotective and antioxidative properties of the new neuroactive peptide cyclo-prolylalanine (DKP-9) were studied on the model of acute cerebral disease (ACD, irreversible bilateral carotid occlusion) in rats. Under the conditions of intranasal administration in the therapeutic mode at the doses 0.02 mg/kg or 0.1 mg/kg peptide DKP-9 has increased rats’ survival rate to 40% or 70% respectively. Increase of the DKP-9 dose to 1 mg/kg reduced the protective effect of it. Peptide DKP-9 has effective decreased the neurological and cognitive deficits in acute period of ACD (4 days) exceeding the reference drug semax (0.1 mg/kg, intranasally in same treatment mode). Under the conditions of open-field test the sedative properties of DKP-9 and also the ability of it to reduce rats’ stress-induced anxious reactions were established. Antioxidative properties of DKP-9 are followed by increase of the reduced glutathione level, normalize of the catalase activity, decrease of the level of lipid peroxidation products as well as increase of the brain neurons’ energy metabolism. The further investigation of mechanism of cyclo-prolylalanine (DKP-9) action on the pathogenic links of ischemic cascade is perspective.
Improvement of Alzheimer's disease (AD) therapy is one of the most important tasks of the modern medicine and pharmacy. Creation and the pharmacological study of the original medicines for treating AD are promising. The most promising class of these drugs is neuroprotectors. In the Research Institute of Highly Pure Biopreparations the tetrapeptide acetyl-(D- day). According to all indices the activity of KK-1 exceeded the reference medicine donepezil. The mechanism of the KK-1 nootropic action is in the increase of the Ach level in the rats' brain synaptosoms probably due to stimulation of its synthesis. The peptide KK-1 moderately inhibits the ACE leading also to the Ach level increase in the cholinergic synapse synaptic cleft. It is likely that the peptide KK-1 has an effect on the G q /G 11 -peptide-coupled М 1 -, М 3 -, and М 5 -cholinergic receptors as a positive allosteric modulator.А ктуальність удоскона-лення нейропротектор-ної терапії хвороб неврологіч-ного профілю зростає. Це пов'я-зано, перш за все, зі збільшен-ням захворюваності населення на цереброваскулярні, нейро-дегенеративні та травматичні патології головного мозку (ГМ) і недостатньою ефективністю існуючих методів лікування.Хвороба Альцгеймера (ХА) являє собою нейродегенера-тивне захворювання, на яке у 2015 році страждало 0,44% на-селення світу, а до 2050 року кількість хворих має зрости вчет-веро [21]. На теперішній час те-рапія ХА здійснюється переваж-но засобами патогенетичного спрямування, які уповільнюють її розвиток або зменшують про-яви основних симптомів. Впро-довж останніх років деякі з цих препаратів (донепезил, ривастиг-мін, мемантин тощо) вивчають-ся на предмет нейропротектор-ної активності, оскільки вста-новлена їх здатність уповіль-нювати загибель центральних холінергічних нейронів. Проте успіх їх використання в клініч-Р.Д.Дейко -магістр фармації, аспірант кафедри фармакології Національного фармацевтичного університету (м. Харків) Т.В.Горбач -канд. біол. наук, доцент кафедри біологічної хімії Харківського національного медичного університету О.О.Колобов -доктор біол. наук, завідувач лабораторії хімії пептидів ФДУП «Державний науково-дослідний інститут особливо чистих біопрепаратів» ФМБА Росії (м. Санкт-Петербург)
Abstract.The aim of study is to evaluate antidepressant-like activity of the new peptidergic neuroprotector acetyl-(D-Lys) -Lys-Arg-Arg-amide, homologous of ACTH 15-18 primary amino acids sequence, that demonstrates nootropic and neuroprotective properties.Using Porsolt swimming test (PST) efficacy of tetrapeptide neuroprotector KK-1 at a single dose of 0.02 mg/kg was investigated on 16 white random bred male rats (body mass equaled 180-220 grams). Imipramine (15 mg/ kg i.p.) was used as a reference drug. Then depression was induced in these rats by reserpine (4 mg/kg, i.p.).The KK-1 (intranasally, i.n.) and imipramine were administered once a day during 3 days until the reserpineinduced depression was reproduced. The indices of rats behavior under the conditions of open-field test (OFT) and PST were evaluated. The influence of both drugs on specific reserpine-induced depressions symptoms (hypothermia and blepharoptosis) was also registered. The results were processed statistically.The tetrapeptide neuroprotector KK-1 reduced immobilization time of rats at PST (statistically significant differences compared with control group), exceeding efficacy of reference drug imipramine. Normalizing of locomotor and exploratory activity in the OFT, decreasing indices of rats helplessness behavior in PST by tetrapeptide neuroprotector KK-1 demonstrates its antagonism with depressive action of reserpine. The tetrapeptide KK-1 showed antidepressant-like action both in intact rats and in rats with the model of reserpineinduced depression. It reduced specific symptoms of depression -hypothermia and blepharoptosis, exceeding the activity of reference drug imipramine.
Cerebrovascular diseases are leading problems of the modern medicine and pharmacy. That is why creation of new neuroprotectors and their introduction into clinical practice is a topical issue. A series of oligopeptides, 15-18 adrenocorticotropic hormone link derivatives has been created. These neuropeptides are compounds with the general formula of Acetyl-Lys-Lys-Arg-Arg-amide. They are nontoxic compounds and resistant to action of blood aminopeptidases. Their composition includes unnatural D-aminoacids and their N-methylated forms. The previous studies have determined their anti-ischemic and nootropic action, and a favourable spectrum of psychotropic properties. The question about mechanisms of the antihypoxic action of compound Acetyl-(D-Lys)-Lys-Arg-Arg-amide (КК-1) remains open. The aim of our investigation is to study effect of neuropeptide KK-1 on the hemodynamic parameters, as well as blood oxygenation against the background of ischemia-reperfusion in the rats' brain. The volume speed of the blood flow in the internal carotid artery, blood pressure in the femoral artery, the central venous pressure and blood oxygenation were measured. The ability of peptide KK-1 to restore the initial level of blood pressure in the femoral artery and central venous pressure within 7 days has been found. The volume speed of the blood flow in the internal carotid artery was sufficient for brain blood supply during all post-ischemic period. The level of blood oxygenation varied from 97% to 98%, tending to the norm. By the effect on the indicators listed neuropeptide KK-1 exceeds the action of the reference drug citicoline. The positive effect of peptide KK-1 on the performance of the system and cerebral blood flow and blood oxygen saturation against the background of cerebral ischemia confirms its anti-ischemic and cerebroprotective effect. The pharmacological drug is promising for further experimental and clinical studies.
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