Ocimum sanctum Linn. Extract Improves Cognitive Deficits in Olfactory Bulbectomized Mice via the Enhancement of Central Cholinergic Systems and VEGF Expression

This study aimed to clarify the antidementia effects of ethanolic extract of Ocimum sanctum Linn. (OS) and its underlying mechanisms using olfactory bulbectomized (OBX) mice. OBX mice were treated daily with OS or a reference drug, donepezil (DNP). Spatial and nonspatial working memory performance was measured using a modified Y maze test and a novel object recognition test, respectively. Brain tissues of the animals were subjected to histochemical and neurochemical analysis. OS treatment attenuated OBX-induced impairment of spatial and nonspatial working memories. OBX induced degeneration of septal cholinergic neurons, enlargement of the lateral ventricles, and suppression of hippocampal neurogenesis. OS and DNP treatment also depressed these histological damages. OS administration reduced ex vivo activity of acetylcholinesterase in the brain. OBX diminished the expression levels of genes coding vascular endothelial growth factor (VEGF) and VEGF receptor type 2 (VEGFR2). Treatment with OS and DNP reversed OBX-induced decrease in VEGF gene and protein expression levels without affecting the expression of the VEGFR2 gene. These results demonstrate that the administration of OS can lessen the cognitive deficits and neurohistological damages of OBX and that these actions are, at least in part, mediated by the enhancement of central cholinergic systems and VEGF expression.

Effects of Simultaneous Reinforcement of Endocannabinoid and Cholinergic Systems on Anxiety-Like Behavior in Mice

ObjectiveAnxiety behavior is regulated by different neurotransmitter systems. There has been no direct relationship between endocannabinoid and cholinergic systems on anxiety in previous studies. This study investigated the effects of each of these systems separately and simultaneously using Donepezil (Cholinesterase inhibitor) and URB-597 (endocannabinoid degrading enzyme inhibitor) on anxiety-like behavior. MethodEighty-eight male mice were divided into eleven groups (n=8) including control (saline), diazepam (0.3 mg /kg), URB-597 (0.1, 0.3, or 1 mg /kg), donepezil (0.5, 1 or 2 mg/kg) and the combination of the two drugs at low, medium and high doses. All treatments were injected intraperitoneally 30 minutes before the elevated plus maze test. ResultsSeparate administration of URB597, donepezil or diazepam increased the number and time spent of open arms compared to the control group. Concurrent administration of URB and donepezil at low, medium and high doses did not change the number of open arms entries compared to the control group, but they reduced the number of entries to the closed arms. ConclusionsThese results suggest that strengthening any cholinergic or endocannabinoid system has anxiolytic effect similar to diazepam. However, the interaction of these two systems has fewer anxiolytic effects compared to the effects of each alone. It seems that these drugs alone may represent a strategy for the treatment of anxiety disorders.

EXPERIMENTAL ACTIVATION OF CENTRAL CHOLINERGIC SYSTEMS IN SIMULATED TRAUMATIC BRAIN INJURY

MEDICINE

A functional logic for neurotransmitter co-release in the cholinergic forebrain pathway

The forebrain cholinergic system has recently been shown to co-release both acetylcholine and GABA. We have discovered that such co-release by cholinergic inputs to the claustrum differentially affects neurons that project to cortical versus subcortical targets. The resulting changes in neuronal gain toggles network efficiency and discriminability of output between two different projection subcircuits. Our results provide a potential logic for neurotransmitter co-release in cholinergic systems.

STATE OF NEUROENDOCRINE SYSTEMS DURING ACTIVATION AND INHIBITION OF CENTRAL CHOLINERGIC SYSTEMS IN BRAIN INJURY

The aim of the study was to determine the state of the neuroendocrine systems during the activation and inhibition of the central cholinergic systems (CChS) in traumatic brain injury (TBI) and their effect on mortality and neurological deficit. TBI was applied by the standard method with the free fall of metal weight on the fixed animal head. 161 white male Wistar rats were divided into three groups: in the 1st group, 0.5 ml of Ringer’s solution was injected intraperitoneally before injury (control), in the 2nd – solution of choline alfoscerate at a dose 6 mg/kg (CChS activation), in the 3rd – solution of biperidene hydrochloride at a dose 0.6 mg/kg (CChS blockade). Neurological deficits were assessed using the 100-point Todd scale. In the blood was determined the content of Adrenocorticotropic (ACTH) and Thyroid-Stimulating Hormones, Corticosterone (Cs), free Thyroxine and Triiodothyronine (fT3) by the enzyme immunoassay. It was established that in the acute period of TBI, post-traumatic stress central hypercortisolism is formed with an increase in blood levels of ACTH and Cs, and central hypothyroidism with a predominant decrease in blood fT3. The CChS activation significantly reduced mortality and neurological deficit, which was accompanied by moderate activation of ACTH and Cs and no effect on the thyroid system. The CChS blockade led to the suppression of the post-traumatic reaction of ACTH and Cs activation and the development of deep central hypothyroidism against the significant neurological deficit. Thus, the important role of CChS in the implementation of the post-traumatic stress reaction of the neuroendocrine system has been established, and the possibility of using pharmacological stimulation of the CNS with central cholinomimetics has been substantiated.

ANALYSIS OF THE ROLE OF CENTRAL CHOLINOREACTIVITY IN EXPERIMENTAL TRAUMATIC BRAIN INJURY

The aim of the research. To study effects of activation and inhibition of the central cholinergic systems (CCS) in traumatic brain injury (TBI). Studied problem. To investigate the influence of the reactivity of the central cholinergic systems on the course of the acute period of traumatic brain injury, in an acute experiment on laboratory animals in vivo. The main scientific results. It was found that in the acute period of TBI (the first three days), both activation and blockade of CCS led to a decrease in mortality, which was statistically confirmed only for their activation. The control group was characterized by the progression of neurological deficit, which was realized due to motor disorders and reflex sphere. Upon activation of the CCS, the degree of neurological deficit was significantly less than in other groups, but, nevertheless, it increased from 48 hours after the injury, as regards behavioral and consciousness disorders. Inhibition of cholinergic systems led to a sharp increase in neurological deficit in all areas immediately after injury, to a greater extent due to reflex disorders. This, together with a high mortality rate, indicated a negative effect of the pharmacological shutdown of CCS in TBI. The area of practical use of the research results. The obtained results will allow a deeper study of the influence of the central cholinergic systems on the course and descent of TBI. To develop effective methods of pharmacological correction in the treatment of patients in the acute period of TBI. Innovative technological product: pathogenetically substantiated medical treatment of the acute period of traumatic brain injury, development of new methods of pharmacological neuroprotection for persons with a priori high risk of injury, development of effective options for reducing mortality and disability from TBI. Scope of the innovative technological product. The important role of CCS in the realization of the response of the central nervous system to TBI was established, and the possibility of using pharmacological stimulation of the central nervous system with cholinomimetics of the central type of action was justified.