Modulation Of Cholinergic Activity Research Articles

Neuroprotective and anti-amnesic effects of Laurus Nobilis essential oil against scopolamine-induced memory deficits in mice brain

Ethnopharmacological relevanceLaurus nobilis L. (Lauraceae family) has been widely used in traditional Tunisian medicine for the treatment of different health problems such as rheumatism and some neurological disorders. AimIn this study, the essential oil obtained from Laurus nobilis L. species from Tunisia (LEO) was studied for its chemical composition and anti-amnesic activities on memory impairment caused by scopolamine injection in mice. The major compounds of LEO oil, 1,8-cineole and, α-terpinyl acetate were docked with AChE (Acetylcholinesterase), using Autodock Vina and Discovery Studio visualizer software. Materials and methodsThe Morris water maze (MWM) tests and the Y maze were used to assess the anti-amnesic effects of LEO in mice with scopolamine-induced memory impairments. In brain tissues, the levels of biomarkers, enzyme activity, and protein expression related to the cholinergic system were measured. ResultsChronic administration of scopolamine led to a significant decline in cognitive performance in both the Morris Water Maze (MWM) and Y maze tests, accompanied by pronounced oxidative damage and a significant increase in acetylcholinesterase activity compared to the other groups. However, compared to the scopolamine group, treatment with LEO (100 mg/kg) significantly enhanced cognitive function and ameliorated the oxidative damage (p < 0.05 versus scopolamine) ConclusionThis study demonstrates the beneficial effect of LEO on scopolamine-induced dementia in mice, potentially achieved through the modulation of cholinergic activity and antioxidant properties. The docking analysis of the major compounds, 1,8-cineole and α-terpinyl acetate, further substantiates their potential as memory enhancers.

Regulation of habenular G-protein gamma 8 on learning and memory via modulation of the central acetylcholine system

Guanine nucleotide binding protein (G protein) gamma 8 (Gng8) is a subunit of G proteins and expressed in the medial habenula (MHb) and interpeduncular nucleus (IPN). Recent studies have demonstrated that Gng8 is involved in brain development; however, the roles of Gng8 on cognitive function have not yet been addressed. In the present study, we investigated the expression of Gng8 in the brain and found that Gng8 was predominantly expressed in the MHb-IPN circuit of the mouse brain. We generated Gng8 knockout (KO) mice by CRISPR/Cas9 system in order to assess the role of Gng8 on cognitive function. Gng8 KO mice exhibited deficiency in learning and memory in passive avoidance and Morris water maze tests. In addition, Gng8 KO mice significantly reduced long-term potentiation (LTP) in the hippocampus compared to that of wild-type (WT) mice. Furthermore, we observed that levels of acetylcholine (ACh) and choline acetyltransferase (ChAT) in the MHb and IPN of Gng8 KO mice were significantly decreased, compared to WT mice. The administration of nAChR α4β2 agonist A85380 rescued memory impairment in the Gng8 KO mice, suggesting that Gng8 regulates cognitive function via modulation of cholinergic activity. Taken together, Gng8 is a potential therapeutic target for memory-related diseases and/or neurodevelopmental diseases.

Moringa oleifera Seed Extract Alleviates Scopolamine-Induced Learning and Memory Impairment in Mice.

The extract of Moringa oleifera seeds has been shown to possess various pharmacological properties. In the present study, we assessed the neuropharmacological effects of 70% ethanolic M. oleifera seed extract (MSE) on cognitive impairment caused by scopolamine injection in mice using the passive avoidance and Morris water maze (MWM) tests. MSE (250 or 500 mg/kg) was administered to mice by oral gavage for 7 or 14 days, and cognitive impairment was induced by intraperitoneal injection of scopolamine (4 mg/kg) for 1 or 6 days. Mice that received scopolamine alone showed impaired learning and memory retention and considerably decreased cholinergic system reactivity and neurogenesis in the hippocampus. MSE pretreatment significantly ameliorated scopolamine-induced cognitive impairment and enhanced cholinergic system reactivity and neurogenesis in the hippocampus. Additionally, the protein expressions of phosphorylated Akt, ERK1/2, and CREB in the hippocampus were significantly decreased by scopolamine, but these decreases were reversed by MSE treatment. These results suggest that MSE-induced ameliorative cognitive effects are mediated by enhancement of the cholinergic neurotransmission system and neurogenesis via activation of the Akt, ERK1/2, and CREB signaling pathways. These findings suggest that MSE could be a potent neuropharmacological drug against amnesia, and its mechanism might be modulation of cholinergic activity via the Akt, ERK1/2, and CREB signaling pathways.

Neuroprotective effects of polygalacic acid on scopolamine-induced memory deficits in mice

BackgroundPolygala tenuifolia Willd is a Traditional Chinese Medicine used for the treatment of learning and memory deficits. Triterpenoid saponins, the main bioactive compounds of Polygala tenuifolia Willd, are easily hydrolyzed to polygalacic acid (PA). PurposeThe present study was undertaken to investigate the neuroprotective effects of PA on scopolamine-induced cognitive dysfunction and to elucidate its underlying mechanisms of action. MethodsPA (3, 6, and 12 mg/kg) was administered orally to mice for fourteen days, and scopolamine (1 mg/kg) was injected intraperitoneally for fourteen days to induce memory impairment. Memory-related behaviors were evaluated using the Morris water maze. Cholinergic and neuroinflammatory activities were measured in brain tissue. Superoxide dismutase activities, malondialdehyde and reduced glutathione contents were also measured in the brains. ResultsTreatment with scopolamine significantly increased the escape latency time, decreased the number of crossings, and shortened the time spent in the target quadrant, while PA reversed these scopolamine-induced effects. PA significantly improved cholinergic system reactivity, as indicated by decreased acetylcholinesterase (AChE) activity, increased choline acetyltransferase (ChAT) activity, and elevated levels of acetylcholine (ACh) in the hippocampus and frontal cortex. PA also significantly ameliorated neuroinflammation and oxidative stress in mice. ConclusionThese results suggest that PA might exert a significant neuroprotective effect on cognitive impairment, driven in part by the modulation of cholinergic activity and neuroinflammation.

Modulation of food consumption and sleep–wake cycle in mice by the neutral CB1 antagonist ABD459

The brain endocannabinoid system is a potential target for the treatment of psychiatric and metabolic conditions. Here, a novel CB1 receptor antagonist (ABD459) was synthesized and assayed for pharmacological efficacy in vitro and for modulation of food consumption, vigilance staging and cortical electroencephalography in the mouse. ABD459 completely displaced the CB1 agonist CP99540 at a Ki of 8.6 nmol/l, and did not affect basal, but antagonized CP55940-induced GTPγS binding with a KB of 7.7 nmol/l. Acute ABD459 (3-20 mg/kg) reliably inhibited food consumption in nonfasted mice, without affecting motor activity. Active food seeking was reduced for 5-6 h postdrug, with no rebound after washout. Epidural recording of electroencephalogram confirmed that ABD459 (3 mg/kg) robustly reduced rapid eye movement (REM) sleep, with no alterations of wakefulness or non-REM sleep. Effects were strongest during 3 h postdrug, followed by a progressive washout period. The CB1 antagonist AM251 (3 mg/kg) and agonist WIN-55,212-2 (WIN-2: 3 mg/kg) also reduced REM, but variously affected other vigilance stages. WIN-2 caused a global suppression of normalized spectral power. AM251 and ABD459 lowered delta power and increased power in the theta band in the hippocampus, but not the prefrontal cortex. The neutral antagonist ABD459 thus showed a specific role of endocannabinoid release in attention and arousal, possibly through modulation of cholinergic activity.

Ethanol extract of Astragali Radix and Salviae Miltiorrhizae Radix, Myelophil, exerts anti-amnesic effect in a mouse model of scopolamine-induced memory deficits

Ethnopharmacological relevanceMyelophil, a combination of extracts taken from Astragali Radix and Salviae Miltiorrhizae Radix, is a traditional Chinese medicine used for the treatment of chronic fatigue-associated disorders. Here we examined the ability of Myelophil to alleviate memory impairment in a mouse model. We aimed to investigate whether Myelophil has the pharmacological effects on memory deficits associated with brain dysfunctions using an animal model. Materials and methodsTen week-old male C57BL/6N mice were pretreated with Myelophil (50, 100, or 200mg/kg), or tacrine (10mg/kg) for 7 days, and then intraperitoneally injected with scopolamine (1mg/kg). Memory-related behaviors were evaluated using the Morris water maze for 5 days. Levels of biomarkers of oxidative stress, antioxidant activity, acetylcholinesterase (AChE) activity, and extracellular signal-regulated kinase (ERK) were measured in brain tissues. ResultsScopolamine treatment increased the escape latency time and shortened time spent in the target quadrant; these effects were ameliorated by pretreatment with Myelophil. Scopolamine-induced changes in reactive oxygen species (ROS), malondialehyde (MDA), and AChE activity were significantly attenuated in mice pretreated with Myelophil. Recovery of antioxidant capacities, including total glutathione (GSH) content, and the activities of GSH-reductase, GSH-S-transferase, and catalase was also evident in Myelophil-treated mice. The strongest effects were seen for ERK and muscarinic acetylcholine receptor 1 (mAChR1) at both the protein and gene expression levels, with significant amelioration of expression levels in the Myelophil pretreatment group. ConclusionsThese results suggest that Myelophil confers anti-amnesic properties in a mouse model of memory impairment, driven in part by the modulation of cholinergic activity.

Pharmacological activation of CB1 receptor modulates long term potentiation by interfering with protein synthesis

Cognitive impairment is one of the most important side effects associated with cannabis drug abuse, as well as the serious issue concerning the therapeutic use of cannabinoids. Cognitive impairments and neuropsychiatric symptoms are caused by early synaptic dysfunctions, such as loss of synaptic connections in different brain structures including the hippocampus, a region that is believed to play an important role in certain forms of learning and memory. We report here that metaplastic priming of synapses with a cannabinoid type 1 receptor (CB1 receptor) agonist, WIN55,212-2 (WIN55), significantly impaired long-term potentiation in the apical dendrites of CA1 pyramidal neurons. Interestingly, the CB1 receptor exerts its effect by altering the balance of protein synthesis machinery towards higher protein production. Therefore the activation of CB1 receptor, prior to strong tetanization, increased the propensity to produce new proteins. In addition, WIN55 priming resulted in the expression of late-LTP in a synaptic input that would have normally expressed early-LTP, thus confirming that WIN55 priming of LTP induces new synthesis of plasticity-related proteins. Furthermore, in addition to the effects on protein translation, WIN55 also induced synaptic deficits due to the ability of CB1 receptors to inhibit the release of acetylcholine, mediated by both muscarinic and nicotinic acetylcholine receptors. Taken together this supports the notion that the modulation of cholinergic activity by CB1 receptor activation is one mechanism that regulates the synthesis of plasticity-related proteins.

Effect of Selective Cholinergic Denervation on the Serotonergic System: Implications for Learning and Memory

The cholinergic system has been widely implicated in cognitive processes and cholinergic loss is a classical hallmark in Alzheimer disease. Increasing evidence supports a role of the serotonergic system in cognition, possibly through a modulation of cholinergic activity. We compared selective cholinergic denervation by administration of the immunotoxin 192 IgG-saporin in the nucleus basalis of Meynert (NBM) with intracerebroventricular (ICV) lesions of the basal forebrain in male rats 7 days after lesioning. NBM lesions induced significant changes in cholinergic markers in the frontal cortex, whereas ICV lesions produced significant decreases in cholinergic markers both in the frontal cortex and hippocampus. Only ICV lesions lead to memory impairments in passive avoidance and Morris water maze tasks. Both models lead to reductions of serotonin levels in the frontal cortex. Similar changes in 5-hydroxytriptophan levels were observed, suggesting a downregulation of the rate-limiting enzyme for the synthesis of serotonin along with the cholinergic deficit. Neither 5-HT1A nor 5-HT1B receptors seem to mediate this process. These data imply that the serotonergic system in the frontal cortex can compensate for diminished cholinergic function and support the investigation of the serotonergic system as a therapeutic target to treat Alzheimer disease.

Relation of cerebral blood flow velocity and level of vigilance in humans.

Blood flow velocities in both middle cerebral arteries (MCA) were measured using transcranial Doppler ultrasound (TCD) in healthy subjects engaged in a continuous static visual vigilance task. Stimuli comprised white vertical gratings on a black background with a size of 5 x 5" (non-targets) or 5 x 3.5" (targets). Button presses were required to the rare (8.5%) targets. Over the 30 min session a decrease in hit rate and an increase in reaction time were seen, indicating a decrease in vigilance. These performance changes were paralleled by a decrease in flow velocity in both MCAs. No hemispheric difference was seen. These data suggest a close coupling of performance and blood flow in vigilance tasks. Modulation of cholinergic activity during the vigilance task might be the common underlying mechanism.

Hypotensive Action of Salvia miltiorrhiza Cell Culture Extract

Salvia miltiorrhiza cell culture extract (SCE) was shown to produce dose-dependent hypotensive response in normo-tensive rats. The mode of this hypotensive action was studied both in vivo and in vitro. This vasodepressor effect was not due to the presence of cations (potassium, calcium and magnesium) in the extract. In pharmacological antagonist studies, the hypotensive effect was shown not being mediated via the alpha-, beta-adrenoceptors, histamine receptors and autonomic ganglion; nor via direct vasodilation and diuresis. However, the vasodepressor effect was probably angiotensin- and/or bradykinin-related since captopril infusion potentiated the hypotensive effect of SCE. Furthermore, data indicated that the vasodepressor effect might be accounted for by the positive inotropic and negative chronotropic effects of SCE, the latter via its modulation of cholinergic activity.

Modulation of cholinergic activity and the aversive threshold in the rat

The analgesic potency of atropine sulfate (5.0, 10.0, 20.0, 40.0 mg/kg), eserine sulfate (0.5, 1.0, 1.5 mg/kg), pilocarpine nitrate (5.0, 10.0, 20.0 mg/kg), scopolamine methylbromide (0.5, 1.0 mg/kg) and scopolamine hydrobromide (1.0 mg/kg) was measured in the rat using the spatial preference technique. Enhanced cholinergic tone via the administration of eserine or pilocarpine in conjunction with scopolamine methylbromide produced significant increments in the aversive threshold. These increments could not be accounted for solely by changes in motor activity or the debilitating effects of enhanced peripheral cholinergic stimulation. None of the anticholinergics tested affected the aversive threshold. Scopolamine hydrobromide (1.0 mg/kg), however, was able to fully block the increments in the aversive threshold noted after the administration of pilocarpine (10.0 mg/kg). These results were interpreted to suggest that agents which enhance cholinergic tone can produce significant analgesia in the rat. While no firm conclusions can be made without further evidence, especially with regard to the antianalgesic effects of the anticholinergics, it is possible that central cholinergic mechanisms may mediate the aversive qualities of electric shock in the rat.