Antinociceptive Effects of Aza-Bicyclic Isoxazoline-Acylhydrazone Derivatives in Different Models of Nociception in Mice

Background: In a study recently published by our research group, the compounds isoxazoline-acylhydrazone derivatives R-99 and R-123 presented promising antinociceptive activity. However, the mechanism of action of this compound is still unknown. Objective: This study aimed to assess the mechanisms involved in the antinociceptive activity of these compounds in chemical models of pain. Methods: Animals were orally pretreated and evaluated in the acetic acid-, formalin-, capsaicin-, carrageenan- and Complete Freund's Adjuvant (CFA)-induced pain models in mice. The effects of the compounds after pretreatment with naloxone, prazosin, yohimbine, atropine, L-arginine, or glibenclamide were studied, using the acetic acid-induced writhing test to verify the possible involvement of opioid, α1-adrenergic, α2-adrenergic or cholinergic receptors, and nitric oxide or potassium channels pathways, respectively. Results: R-99 and R-123 compounds showed significant antinociceptive activity on pain models induced by acetic acid, formalin, and capsaicin. Both compounds decreased the mechanical hyperalgesia induced by carrageenan or CFA in mice. The antinociceptive effects of R-99 and R-123 on the acetic acid-induced writhing test were significantly attenuated by pretreatment with naloxone, yohimbine or atropine. R-99 also showed an attenuated response after pretreatment with atropine and glibenclamide. However, on the pretreatment with prazosin, there was no change in the animals' response to both compounds. Conclusion: R-99 and R-123 showed antinociceptive effects related to mechanisms that involve, at least in part, interaction with the opioid and adrenergic systems and TRPV1 pathways. The compound R-99 also interacts with the cholinergic pathways and potassium channels.

Severity of Lesions Involving the Cortical Cholinergic Pathways May Be Associated With Cognitive Impairment in Subacute Ischemic Stroke

Purpose: Impairment of cortical cholinergic pathways (CCP) is an important risk factor for chronic vascular cognitive impairment. However, this phenomenon has rarely been studied in post-stroke cognitive impairment (PSCI). We investigated the relationship between PSCI and CCP lesions assessed by structural magnetic resonance imaging (MRI).Patients and methods: We prospectively enrolled 103 patients within 7 days of ischemic stroke onset. CCP was measured by the cholinergic pathways hyperintensities scale (CHIPS), which semiquantitatively grades MR lesions strategically located on the CCP identified in human brains. We also measured other MRI parameters, including the location and volumes of acute infarcts, cerebral microbleeds, medial temporal lobe atrophy, and white matter lesions. Neuropsychological assessments were performed using the 60-min modified vascular dementia battery (VDB) at 3 months after the index stroke, and PSCI was defined according to VDB as well as ADL.Results: Of all 103 patients, 69 men (67.0%) and 34 women (33.0%) with a mean age of 57.22 ± 12.95 years, 55 patients (53.4%) were judged to have PSCI at 3 months, including 43 (41.7%) patients with PSCI-no dementia and 12 (11.7%) patients with poststroke dementia. According to the VBD assessment, the most commonly impaired cognitive domain was visuomotor speed (27.2%) followed by verbal memory (25.2%). Univariate analysis showed that patients with PSCI were older; had higher informant questionnaire on cognitive decline in the elderly (IQCODE) scores; had more frequent previous stroke history and atrial fibrillation; and had higher CHIPS scores, more severe white matter lesions, and medial temporal lobe atrophy. PSCI patients also had higher depression scores at 3 months. In the multivariate regression analysis, age, IQCODE score, CHIPS score, and Hamilton depression rating scale score were independent predictors of PSCI. Ordinal regression analysis for risk factors of poor functional outcomes revealed that IQCODE scores and cognitive function status were related to mRS score at 3 months after stroke.Conclusion: In patients with early subacute ischemic stroke, the severity of lesions involving the CCP may be associated with cognitive impairment at 3 months.Clinical Trial Registration: Chinese Clinical Trial Registry, identifier: ChiCTR1800014982.

Quercetin action on pain modulation/ Ação da quercetina sobre a modulação da dor

Background: Quercetin is a flavonoid widely found in plant kingdom and target of studies in pharmacological area due to its potent antinociceptive effect compared to analgesics used in conventional therapies. The aim was to evaluate its antinociceptive activity and antinociception mechanism. Methods: For this, 40 Norvegicus Wistar rats were used, divided into 4 groups: Q50 (treated with quercetin 50 mg/Kg), Q100 (treated with quercetin 100 mg/Kg), Q500 (treated with quercetin 500 mg/Kg) and Positive control (PC) without quercetin treatment), who were submitted through the pain induction methods by tail immersion and formalin in the first step to assess antinociceptive action and in the second step, tail immersion method receiving antagonists from opioid, cholinergic and nitric oxide - L-arginine to evaluate the action mechanism. Results: Quercetin antinociceptive activity was verified at the dose of 50 mg/kg and 100 mg/kg in tail immersion test after formalin injection, with better performance at the dose of 50 mg/kg. There were no statistically significant results in paw opening and capsaicin tests. Quercetin demonstrated a possible influence on opioid and cholinergic pathway, which was not observed on the nitric acid - L-arginine pathway in view of parameters tested. Conclusion: Quercetin performed the best antinociceptive activity at a dose 50 mg/kg and there was a possible influence on opioid and cholinergic pathways.

In silico Gene Set and Pathway Enrichment Analyses Highlight Involvement of Ion Transport in Cholinergic Pathways in Autism: Rationale for Nutritional Intervention

Food is the primary human source of choline, an essential precursor to the neurotransmitter acetylcholine, which has a central role in signaling pathways that govern sensorimotor functions. Most Americans do not consume their recommended amount of dietary choline, and populations with neurodevelopmental conditions like autism spectrum disorder (ASD) may be particularly vulnerable to consequences of choline deficiency. This study aimed to identify a relationship between ASD and cholinergic signaling through gene set enrichment analysis and interrogation of existing database evidence to produce a systems biology model. In gene set enrichment analysis, two gene ontologies were identified as overlapping for autism-related and for cholinergic pathways-related functions, both involving ion transport regulation. Subsequent modeling of ion transport intensive cholinergic signaling pathways highlighted the importance of two genes with autism-associated variants: GABBR1, which codes for the gamma aminobutyric acid receptor (GABAB1), and KCNN2, which codes for calcium-activated, potassium ion transporting SK2 channels responsible for membrane repolarization after cholinergic binding/signal transmission events. Cholinergic signal transmission pathways related to these proteins were examined in the Pathway Studio environment. The ion transport ontological associations indicated feasibility of a dietary choline support as a low-risk therapeutic intervention capable of modulating cholinergic sensory signaling in autism. Further research at the intersection of dietary status and sensory function in autism is warranted.

Autonomic and cholinergic mechanisms mediating cardiovascular and temperature effects of donepezil in conscious mice

Donepezil is a centrally-acting acetylcholinesterase (AChE) inhibitor with therapeutic potential in inflammatory diseases; however, the underlying autonomic and cholinergic mechanisms remain unclear. Here, we assessed effects of donepezil on mean arterial pressure (MAP), heart rate (HR), HR variability, and body temperature in conscious adult male C57BL/6 mice to investigate the autonomic pathways involved. Central vs. peripheral cholinergic effects of donepezil were assessed using pharmacological approaches including comparison with the peripherally-acting AChE inhibitor, neostigmine. Drug treatments included donepezil (2.5 or 5 mg/kg s.c.), neostigmine methyl sulfate (80 or 240 μg/kg i.p.), atropine sulfate (5 mg/kg i.p.), atropine methyl bromide (5 mg/kg i.p.), or saline. Donepezil, at 2.5 and 5 mg/kg, decreased HR by 36±4 and 44±3% compared to saline (n=10, P<0.001). Donepezil, at 2.5 and 5 mg/kg, decreased temperature by 13±2 and 22±2% compared to saline (n=6, P<0.001). Modest (P<0.001) increases in MAP were observed with donepezil after peak bradycardia occurred. Atropine sulfate and atropine methyl bromide blocked bradycardic responses to donepezil, but only atropine sulfate attenuated hypothermia. The pressor response to donepezil was similar in mice co-administered atropine sulfate; however, co-administration of atropine methyl bromide potentiated the increase in MAP. Neostigmine did not alter HR or temperature but did result in early increases in MAP. Despite the marked bradycardia, donepezil did not increase normalized high frequency HR variability. We conclude that donepezil causes marked bradycardia and hypothermia in conscious mice via activation of muscarinic receptors while concurrently increasing MAP via autonomic and cholinergic pathways that remain to be elucidated.

Disrupted metabolic connectivity in dopaminergic and cholinergic networks at different stages of dementia from 18F-FDG PET brain persistent homology network

Dementia is related to the cellular accumulation of β-amyloid plaques, tau aggregates, or α-synuclein aggregates, or to neurotransmitter deficiencies in the dopaminergic and cholinergic pathways. Cellular and neurochemical changes are both involved in dementia pathology. However, the role of dopaminergic and cholinergic networks in metabolic connectivity at different stages of dementia remains unclear. The altered network organisation of the human brain characteristic of many neuropsychiatric and neurodegenerative disorders can be detected using persistent homology network (PHN) analysis and algebraic topology. We used 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging data to construct dopaminergic and cholinergic metabolism networks, and used PHN analysis to track the evolution of these networks in patients with different stages of dementia. The sums of the network distances revealed significant differences between the network connectivity evident in the Alzheimer’s disease and mild cognitive impairment cohorts. A larger distance between brain regions can indicate poorer efficiency in the integration of information. PHN analysis revealed the structural properties of and changes in the dopaminergic and cholinergic metabolism networks in patients with different stages of dementia at a range of thresholds. This method was thus able to identify dysregulation of dopaminergic and cholinergic networks in the pathology of dementia.

Potential Phyto Therapeutic Approaches for the Treatment of Alzheimer’s Disease: An Overview

: Alzheimer’s disease is one of the most prevailing age-dependent neurodegenerative disease and the most common cause of dementia. The pharmacological therapies available for the disease provide only symptomatic relief. Plants are being extensively investigated for Alzheimer’s as they are relatively safer and cheaper. This review summarizes recent findings suggesting anti-Alzheimer potential of the plants along with compounds or mechanisms responsible for their efficacy and their therapeutic targets. The findings of recent studies revealed that the plants or the compounds isolated from them exhibit mitigative potential in Alzheimer’s disease by targeting amyloid beta, tau protein, cholinergic pathways via various enzymes like beta secretase, gamma secretase, acetylcholinesterase or receptors involved in these pathways. A number of putative compounds revealed from these studies can be investigated further for the mitigation of Alzheimer’s disease.

Antidepressant effect of methanol stem bark extract of Adansonia digitata: involvement of monoaminergic, nitric oxide and cholinergic pathways

Introduction: Hausa people of north-western Nigeria were reported to utilize the plant Adansonia digitata for the management of depressive illnesses in an ethnobotanical survey. Thus, this study aimed to establish the mechanism(s) via which methanol stem bark extract of A. digitata (MEAD) exhibits antidepressant activity in mice. Methods: Antidepressant activity of MEAD was evaluated using tail suspension test (TST) at doses of 250, 500 and 1000 mg/kg. For the mechanistic studies, mice were pre-treated with sulpiride (50 mg/kg), prazosin (1 mg/kg), yohimbine (1 mg/kg), metergoline (1 mg/kg), cyproheptadine (3 mg/kg), L-arginine (50 mg/kg), N omega-nitro-L-arginine (L-NNA; 50 mg/kg), atropine (1 mg/kg) and naloxone (2 mg/kg) 15 minutes prior to MEAD (1000 mg/kg) administration, then antidepressant activity was assessed using TST one hour later. Data were analyzed using one-way ANOVA followed by Bonferroni post hoc test. Results: The extract (at doses of 250, 500 and 1000 mg/kg) significantly (P < 0.05) and dose-dependently decreased the duration of immobility in the TST. Sulpiride (D2 receptor antagonist), prazosin and yohimbine (α1 and α2 receptor antagonists, respectively), metergoline and cyproheptadine (5-HT1 and 5-HT2 receptor antagonists, respectively) significantly (P < 0.05) reversed the antidepressant effect of MEAD. On the other hand, L-NNA (NOS inhibitor) augmented the antidepressant effect of MEAD while L-arginine (nitric oxide substrate) had no effect on MEAD. However, atropine (muscarinic receptor antagonist) significantly (P < 0.01) augmented the antidepressant effect of MEAD. Conclusion: The antidepressant activity of methanol stem bark extract of A. digitata was established to be via the monoaminergic, nitric oxide and cholinergic pathways.