The article presents the results of studying the neuroprotective activity of carboxylic acid diamides under conditions of focal cerebral ischemia. The study was carried out on male Wistar rats, which underwent focal ischemia by irreversible occlusion of the right middle cerebral artery. The compounds under study under the codes FacAc, FacPr, FisBut, Faib, the reference drug piracetam were injected intragastrically on the next day after the operation at a dose of 100 mg/kg and then for three days. The neuroprotective activity of the compounds was studied using models for assessing memory and cognitive functions -the technique of avoiding passive (CPAR) and active (EMT) environments, and also studied the effect of compounds on the size of the necrosis zone. In the course of the study, it was found that, against the background of focal cerebral ischemia, the use of diamides of carboxylic acids contributed to the preservation of the memory trace in rats, as well as the necrosis zone. The results of experimental data indicate the possibility of further in-depth study of the compounds under study under laboratory codes FacAc, FacPr, FisBut, Faib for neuroprotective activity.
INTRODUCTION: Uncontrolled course of apoptosis reactions underlies a wide range of pathological processes, including ischemic events. AIM: To evaluate the anti-apoptotic properties of some racetams in experimental brain ischemia in rats. MATERIALS AND METHODS: Cerebral ischemia was modeled in Wistar rats by irreversible occlusion of the middle cerebral artery. The test-compounds and the reference drug piracetam were administered per os at a dose of 250 mg/kg. After 72 hours of the ischemic period, the activity of apoptotic systems in the brain tissue was evaluated by determining the concentration of the apoptotic-inducing factor (AIF), caspase-3, ionized calcium, the latent opening time of the mitochondrial transition permeability pore and the zone of brain necrosis. RESULTS: The study showed that the use of the studied compounds contributed to a decrease in the intensity of reactions, both caspase-dependent and caspase-independent apoptosis, which was reflected in a decrease in the concentration of AIF and caspase-3 by 32.4% (p < 0.05); 34.6% (p < 0.05); 31.1% (p < 0.05), and 41.9% (p < 0.05); 39.1% (p < 0.05); 34.5% (p < 0.05) when PirPr, PirAc and PirBut were administered, respectively. Also, the use of the studied substances led to an increase in the latent period of opening the mitochondrial transition permeability pore, a decrease in the concentration of intracellular calcium and the zone of brain necrosis. At the same time, the pharmacological effect of the administration of the compound PirAc exceeded the effect of piracetam and other test substances. CONCLUSIONS: Based on the results obtained, it can be assumed that the studied racetams have neuroprotective action, realized through suppression of the reactions of apoptosis.
The aim of the present study was to assess safety and clinical efficacy of inhalation immunotherapy based on intranasal administration of bioactive factors produced by the M2 phenotype macrophages in children with language impairments, as well as to study the effect of inhalation immunotherapy on the cytokine profile in the patients' blood serum. The study was carried out according to the NCT04689282 protocol (www.ClinicalTrials.gov) and included 14 children (9 boys / 5 girls), aged 3 to 8 years, with language impairments associated with perinatal or postnatal CNS lesions of various origin. The children recruited into the study were assessed by a neurologist and speech therapist before the therapy, at the end of the course (1 month), and 6 months later. Serum samples for cytokine analysis were obtained before and 1 month after therapy. The course of intranasal inhalations by the conditioned M2 media (2 ml one time per day for 28-30 days) was safe and well tolerated. None of the 14 treated children had significant adverse reactions and severe undesirable events. Intranasal immunotherapy led to a decrease in the severity of language problems, which manifested by improved speech understanding by 45%; the sensorimotor level of speech, by 51%; word formation skills, by 72%, as well as a twofold increase in general and fine motor skills. In children with signs of autism spectrum disorders, along with a language improvement, a decrease in the severity of autistic symptoms was registered, as evidenced by statistically significant decrease in the CARS score from 42.5 to 38.5 after 1 month, and to 33 points after 6 months (p < 0.05). The clinical effect was revealed rather soon, i.e., within a month after the first procedure, being maintained or intensified during a follow-up for 6 months. At the same time, two-thirds of the children showed a clear clinical improvement, with insignificant effect in the rest of patients. Comparative analysis of the serum cytokine levels in these subgroups showed that children with a pronounced positive response to inhaled immunotherapy differed in the following parameters: (1) initially higher level of VEGF and IGF-1, and (2) decrease the level of TNFα in response to intranasal immunotherapy. In summary, we first tested a fundamentally new approach based on the use of soluble factors from M2-type macrophages and intranasal route of their administration in order to treat the children with severe language impairments, demonstrating safety and obtained preliminary data on effectiveness of such approach.
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