Cortical Acetylcholinesterase Research Articles

Hippocampal acetylcholinesterase activation induced by streptozotocin in mice is protected by an organotellurium compound without evidence of toxicity.

The cognitive deficit, which is like Alzheimer's disease and is associated with oxidative damage, may be induced by exposure to streptozotocin. This study aimed to evaluate if the tellurium-containing organocompound, 3j, 5'-arylchalcogeno-3-aminothymidine derivative, interferes with the effects of streptozotocin, as well as to investigate its toxicity in adult mice. Cognitive deficit was induced by two doses of streptozotocin (2.25 mg/kg/day, 48 h interval) intracerebroventricularly. After, the mice were subcutaneously treated with 3j (8.62 mg/kg/day) for 25 days. The effects were assessed by evaluating hippocampal and cortical acetylcholinesterase and behavioral tasks. 3j toxicity was investigated for 10 (0, 21.55, or 43.10 mg/kg/day) and 37 (0, 4.31, or 8.62 mg/kg/day) days by assessing biometric parameters and glucose and urea levels, and alanine aminotransferase activity in blood plasma. 3j exposure did not alter the behavioral alterations induced by streptozotocin exposure. On the other hand, 3j exposure normalized hippocampus acetylcholinesterase activity, which is enhanced by streptozotocin exposure. Toxicity evaluation showed that the administration of 3j for either 10 or 37 days did not cause harmful effects on the biometric and biochemical parameters analyzed. Therefore, 3j does not present any apparent toxicity and reverts acetylcholinesterase activity increase induced by streptozotocin in young adult mice.

Progression of brain cholinergic dysfunction in patients with isolated rapid eye movement sleep behavior disorder.

Reduced cortical acetylcholinesterase activity, as measured by 11 C-donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD. Twelve iRBD patients underwent 11 C-donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). Cognitive function was rated using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). From baseline to follow-up, the mean 11 C-donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11 C-donepezil DVR. Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores.

Structural and molecular cholinergic imaging markers of cognitive decline in Parkinson's disease.

Cognitive decline in Parkinson's disease is related to cholinergic system degeneration, which can be assessed in vivo using structural MRI markers of basal forebrain volume and PET measures of cortical cholinergic activity. In the present study we aimed to examine the interrelation between basal forebrain degeneration and PET-measured depletion of cortical acetylcholinesterase activity as well as their relative contribution to cognitive impairment in Parkinson's disease. This cross-sectional study included 143 Parkinson's disease participants without dementia and 52 healthy control participants who underwent structural MRI, PET scanning with 11C-methyl-4-piperidinyl propionate (PMP) as a measure of cortical acetylcholinesterase activity, and a detailed cognitive assessment. Based on the fifth percentile of the overall cortical PMP PET signal from the control group, people with Parkinson's disease were subdivided into a normo-cholinergic (n = 94) and a hypo-cholinergic group (n = 49). Volumes of functionally defined posterior and anterior basal forebrain subregions were extracted using an established automated MRI volumetry approach based on a stereotactic atlas of cholinergic basal forebrain nuclei. We used Bayesian t-tests to compare basal forebrain volumes between controls, and normo- and hypo-cholinergic Parkinson's participants after covarying out age, sex and years of education. Associations between the two cholinergic imaging measures were assessed across all people with Parkinson's disease using Bayesian correlations and their respective relations with performance in different cognitive domains were assessed with Bayesian ANCOVAs. As a specificity analysis, hippocampal volume was added to the analysis. We found evidence for a reduction of posterior basal forebrain volume in the hypo-cholinergic compared to both normo-cholinergic Parkinson's disease [Bayes factor against the null model (BF10) = 8.2] and control participants (BF10 = 6.0), while for the anterior basal forebrain the evidence was inconclusive (BF10 < 3). In continuous association analyses, posterior basal forebrain volume was significantly associated with cortical PMP PET signal in a temporo-posterior distribution. The combined models for the prediction of cognitive scores showed that both cholinergic markers (posterior basal forebrain volume and cortical PMP PET signal) were independently related to multi-domain cognitive deficits, and were more important predictors for all cognitive scores, including memory scores, than hippocampal volume. We conclude that degeneration of the posterior basal forebrain in Parkinson's disease is accompanied by functional cortical changes in acetylcholinesterase activity and that both PET and MRI cholinergic imaging markers are independently associated with multi-domain cognitive deficits in Parkinson's disease without dementia. Comparatively, hippocampal atrophy only seems to have minimal involvement in the development of early cognitive impairment in Parkinson's disease.

Vitamin D alleviates cognitive dysfunction and brain damage induced by copper sulfate intake in experimental rats: focus on its combination with donepezil.

This study aimed to demonstrate the potential benefits of donepezil (DPZ) and vitamin D (Vit D) in combination to counteract the neurodegenerative disorders induced by CuSO4 intake in experimental rats. Neurodegeneration (Alzheimer-like) was induced in twenty-four male Wistar albino rats by CuSO4 supplement to drinking water (10mg/L) for 14weeks. AD rats were divided into four groups: untreated AD group (Cu-AD) and three treated AD groups; orally treated for 4weeks with either DPZ (10mg/kg/day), Vit D (500IU/kg/day), or DPZ + Vit D starting from the 10th week of CuSO4 intake. Another six rats were used as normal control (NC) group. The hippocampal tissue content of β-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 and the cortical content of acetylcholine (Ach), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured. Cognitive function tests (Y-maze) and histopathology studies (hematoxylin and eosin and Congo red stains) and immunohistochemistry for neurofilament. Vit D supplementation alleviated CuSO4-induced memory deficits including significant reduction hippocampal BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α and cortical AChE and MDA. Vit D remarkably increased cortical Ach, TAC, and hippocampal Bcl-2. It also improved neurobehavioral and histological abnormalities. The effects attained by Vit D treatment were better than those attained by DPZ. Furthermore, Vit D boosted the therapeutic potential of DPZ in almost all AD associated behavioral and pathological changes. Vit D is suggested as a potential therapy to retard neurodegeneration.

Progression of regional cortical cholinergic denervation in Parkinson's disease.

Cortical cholinergic deficits contribute to cognitive decline and other deficits in Parkinson's disease. Cross-sectional imaging studies suggest a stereotyped pattern of posterior-to-anterior cortical cholinergic denervation accompanying disease progression in Parkinson's disease. We used serial acetylcholinesterase PET ligand imaging to characterize the trajectory of regional cholinergic synapse deficits in Parkinson's disease, testing the hypothesis of posterior-to-anterior progression of cortical cholinergic deficits. The 16 Parkinson's disease subjects (4 females/12 males; mean age: 64.4 ± 6.7 years; disease duration: 5.5 ± 4.2 years; Hoehn & Yahr stage: 2.3 ± 0.6 at entry) completed serial 11C-methyl-4-piperidinyl propionate acetylcholinesterase PET scans over a 4-8 year period (median 5 years). Three-dimensional stereotactic cortical surface projections and volume-of-interest analyses were performed. Cholinergic synapse integrity was assessed by the magnitude, k 3, of acetylcholinesterase hydrolysis of 11C-methyl-4-piperidinyl propionate. Based on normative data, we generated Z-score maps for both the k 3 and the k 1 parameters, the latter as a proxy for regional cerebral blood flow. Compared with control subjects, baseline scans showed predominantly posterior cortical k 3 deficits in Parkinson's disease subjects. Interval change analyses showed evidence of posterior-to-anterior progression of cholinergic cortical deficits in the posterior cortices. In frontal cortices, an opposite gradient of anterior-to-posterior progression of cholinergic deficits was found. The topography of k 3 changes exhibited regionally specific disconnection from k 1 changes. Interval-change analysis based on k 3/k 1 ratio images (k 3 adjustment for regional cerebral blood flow changes) showed interval reductions (up to 20%) in ventral frontal, anterior cingulate and Brodmann area 6 cortices. In contrast, interval k 3 reductions in the posterior cortices, especially Brodmann areas 17-19, were largely proportional to k 1 changes. Our results partially support the hypothesis of progressive posterior-to-cortical cholinergic denervation in Parkinson's disease. This pattern appears characteristic of posterior cortices. In frontal cortices, an opposite pattern of anterior-to-posterior progression of cholinergic deficits was found. The progressive decline of posterior cortical acetylcholinesterase activity was largely proportional to declining regional cerebral blood flow, suggesting that posterior cortical cholinergic synapse deficits are part of a generalized loss of synapses. The disproportionate decline in regional frontal cortical acetylcholinesterase activity relative to regional cerebral blood flow suggests preferential loss or dysregulation of cholinergic synapses in these regions. Our observations suggest that cortical cholinergic synapse vulnerability in Parkinson's disease is mediated by both diffuse processes affecting cortical synapses and processes specific to subpopulations of cortical cholinergic afferents.

Age and Anterior Basal Forebrain Volume Predict the Cholinergic Deficit in Patients with Mild Cognitive Impairment due to Alzheimer's Disease.

Early and severe neuronal loss in the cholinergic basal forebrain is observed in Alzheimer's disease (AD). To date, cholinomimetics play a central role in the symptomatic treatment of AD dementia. Although basic research indicates that a cholinergic deficit is present in AD before dementia, the efficacy of cholinomimetics in mild cognitive impairment (MCI) remains controversial. Predictors of cholinergic impairment could guide individualized therapy. To investigate if the extent of the cholinergic deficit, measured using positron emission tomography (PET) and the tracer 11C-N-methyl-4-piperidyl acetate (MP4A), could be predicted from the volume of cholinergic basal forebrain nuclei in non-demented AD patients. Seventeen patients with a high likelihood of MCI due to AD and 18 age-matched cognitively healthy adults underwent MRI-scanning. Basal forebrain volume was assessed using voxel-based morphometry and a cytoarchitectonic atlas of cholinergic nuclei. Cortical acetylcholinesterase (AChE) activity was measured using MP4A-PET. Cortical AChE activity and nucleus basalis of Meynert (Ch4 area) volume were significantly decreased in MCI. The extent of the cholinergic deficit varied considerably across patients. Greater volumes of anterior basal forebrain nuclei (Ch1/2 area) and younger age (Spearman's rho(17) = -0.596, 95% -CI [-0.905, -0.119] and 0.593, 95% -CI [0.092, 0.863])) were associated with a greater cholinergic deficit. Data suggest that less atrophy of the Ch1/2 area and younger age are associated with a more significant cholinergic deficit in MCI due to AD. Further investigations are warranted to determine if the individual response to cholinomimetics can be inferred from these measures.

Chronic Administration of Combined Oral Contraceptive Pill Causes Prefrontal Cortical Oxidative Stress in Female Wistar Rats

Combined oral contraceptive pill (COCP) is used by women to prevent ovulation. This study investigated toxicological effects of COCP on the brain of female rats. Fifteen rats were divided at random into three groups (n=5): Normal control, and first and second cycles treated orally with COCP (0.04 μg/kg bwt of ethinyl oestradiol and 2 μg/kg bwt levonorgestrel) daily for 21 and 42 days respectively. Toxicological effect of treatment on the brain was assessed in the prefrontal cortical acetylcholinesterase, sodium/potassium-ATPase (Na+/K+-ATPase), superoxide dismutase and catalase activities, lipid peroxidation and reduced glutathione levels. Histomorphological examination of the prefrontal cortex of the rats in all the groups was carried out. Activities of cortical Na+/K+-ATPase, acetylcholinesterase, superoxide dismutase and catalase were significantly (p&lt;0.05) reduced following chronic administration of COCP. Histomorphological study of the pre-frontal cortex showed large pyramidal neurons, pyknotic pyramidal neurons, condensed nuclei and increased perineural spaces. Results showed that chronic administration of oral contraceptive caused prefrontal cortical oxidative stress by repressing activities of antioxidant enzymes, Na+/K+-ATPase and acetylcholinesterase.

Oral administration of Byrophyllum pinnatum flavonoid ameliorates cognitive impairment via modulating cortical neurochemicals and oxidative stress in aluminum chloride‐induced Alzheimer’s disease‐like condition in wistar rats

AbstractBackgroundAluminum, a potent neurotoxicant is a major risk factor involved in the perturbation of neurochemicals leading to the development and progression of Alzheimer’s disease. Byrophyllum pinnatum is widely distributed in Southern Nigeria and used locally for the treatment of various ailments including neurological disorders. This study was aimed to access the neuro restorative potential of B. pinnatum flavonoids (BPF) in aluminum chloride (AlCl3)‐induced AD‐like condition in Wistar ratsMethods B. pinnatum flavonoids were characterized using FTIR and ultra‐high‐performance Liquid chromatography coupled with a mass spectrometry UPLC‐MS/MS. Thirty (30) male adult Wistar rats were used in this study and divided into five groups (n=6). Symptoms mimicking AD were induced in rats by administering 150mg/kg b.w of AlCl3 orally for 21 days. After the induction, animals were divided into five groups (n=6) and treated with BPF (50 and 100 mg/kg body weight) and 3 mg/kg of Rivastigmine for another 21 days. Neuro behavioral activities were assessed using Morris water maze tasks. Acetyl‐cholinesterase (AChE), BACE‐1 and oxidative stress markers were assessed following standard protocols. Semi‐quantitative reverse transcriptase‐PCR (RT‐PCR) was used to access the expression patterns of AChE and BACE‐1 mRNA in the cortex of rats.ResultsCharacterization of BPF revealed the presence of flavonols and flavone as the major constituents. Furthermore, AlCl3 overload caused behavioral alterations and showed impaired cognitive function similar to AD alongside increased brain cortical AChE activity, MDA level and decrease in antioxidant enzymes. In addition, AlCl3 induction caused the up‐regulation of AChE and BACE‐1 mRNA expressions in the cortex of rats. Conversely, oral administration of BPF (50 and 100 mg/kg body weight) significantly ameliorated cognitive deficits, restored oxidant‐antioxidant balance and modulated neurochemical markers, as evidenced by the improvement in brain function. Besides, BPF contributed towards the down‐regulation of AlCl3‐increased AChE and BACE‐1 mRNA expressions in the cortex.ConclusionThe current work demonstrates the therapeutic potential of B. pinnatum and suggests that it can ameliorate cognitive impairment caused by AlCl3 through reverting oxidative stress, restoring neurochemical function.

Cortical cholinergic dysfunction correlates with microglial activation in the substantia innominata in REM sleep behavior disorder

IntroductionIn vivo PET studies in patients with isolated REM sleep behavior disorder (iRBD) have shown presence of neuroinflammation (microglial activation) in the substantia nigra, and reduced cortical acetylcholinesterase activity, suggestive of cholinergic dysfunction, that was more widespread in patients with poorer cognitive performances. This study aimed to explore whether reduced cortical acetylcholinesterase activity in iRBD is linked to microglial activation in the substantia innominata (SI), the major source of cholinergic input to the cortex. MethodsWe used 11C(R)-PK11195 and 11C-Donepezil PET to assess levels of activated microglia and cholinergic function, respectively, in 19 iRBD patients. 11C(R)-PK11195 binding potential (BPND) and 11C-Donepezil distribution volume ratio (DVR) values were correlated using the Pearson statistic. ResultsWe found that a lower cortical 11C-Donepezil DVR correlated with a higher 11C(R)-PK11195 BPND in the SI (r = −0.48, p = 0.04). At a voxel level, the strongest negative correlations were found in the frontal and temporal lobes. ConclusionOur results suggest that reduced cortical acetylcholinesterase activity observed in our iRBD patients could be linked to the occurrence of neuroinflammation in the SI. Early modulation of microglial activation might therefore preserve cortical cholinergic functions in these patients.

Amelioration of diabetes-induced cognitive impairment by Transient Receptor Potential Vanilloid 2 (TRPV2) channel inhibitor: Behavioral and mechanistic study

Transient receptor potential (TRP) channels are Ca2+ permeable non-selective cation channels which play a pivotal role in diabetes and diabetic complications. Among diabetic complications, diabetes-induced cognitive impairment is a major CNS complication. The role of several TRP channels has been investigated extensively for their diverse Ca2+ regulating mechanism, and recently their role has been postulated in the progression of neurodegenerative disorders. However, the role of TRPV2 has not been investigated yet. Therefore, in the present study, the involvement of TRPV2 channels was investigated in diabetes-induced cognitive impairment using TRPV2 inhibitor, tranilast. High glucose exposure in rat C6 glial cells enhances the Ca2+-entry through TRPV2 channels. In our in-vivo study, diabetic rats showed increased gene and protein expression of TRPV2 in the hippocampus. Subsequent increase in the acetylcholinesterase activity in the cortex, as well as decrease in the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (p-CaMKII-Thr-286), p-GSK-3β (Ser-9), p-CREB (Ser-133) and postsynaptic density protein 95 (PSD-95) in the hippocampus were also observed this led to the impairment in the learning and memory as evident from behavioral parameters such as Morris water maze test, passive avoidance and Y-maze test paradigm. Three-week treatment with tranilast (30 and 100 mg/kg, p.o.) showed improvement in learning and memory associated behaviours (Morris water maze test, passive avoidance, and Y-maze test) by increasing the p-CaMKII (Thr-286), p-GSK-3β (Ser-9), p-CREB (Ser-133) and PSD-95 in the hippocampus. Cortical acetylcholinesterase activity was also reduced by the tranilast. These findings depicted that TRPV2 inhibition may be an effective treatment strategy in diabetes-induced cognitive deficits.

Antidepressant-like effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one in rats exposed to malathion: Involvement of BDNF-Trkβ pathway and AChE

BackgroundOrganophosphorus pesticides exert their toxic effects mainly by the inhibition of acetylcholinesterase (AChE), which is related to emotional disorders, such as depression. Atropine-oximes therapy is commonly used; however, the efficacy of oximes in the reactivation of AChE has been inconsistent. The objective of this study was to investigate the possible neuroprotective effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cℓ-HIN), a compound that combines the isatin and oxime functional groups, in rats exposed to malathion. The effect of Cℓ-HIN on the AChE activity and the BDNF-Trkβ pathway in the prefrontal cortex of malathion-exposed rats were tested. MethodsWistar male rats were co-treated with Cℓ-HIN [50 mg/kg (p.o.) (3 mL/kg)] and/or malathion [250 mg/kg (i.p.) (5 mL/kg)] and performed behavioral tests twelve hours after these exposures. ResultsThe Cℓ-HIN reversed the increased immobility time in the forced swimming test and the decreased grooming time in the splash test induced by malathion, but any significant difference was observed in locomotion analysis. These results demonstrate the antidepressant-like effect of Cℓ-HIN. The cortical AChE activity was reactivated by Cℓ-HIN in rats exposed to malathion. Malathion induced an increase in Trkβ and a decrease in BDNF levels in the prefrontal cortex of rats, which were avoided by Cℓ-HIN. ConclusionThese findings support the hypothesis that Cℓ-HIN is an AChE reactivator with antidepressant-like properties, which is related to the improvement of BDNF-Trkβ signaling after acute exposure to malathion in rats. Thus, the results allow suggesting the potential use of Cℓ-HIN as an oxime-based therapy against the neurotoxic effects of malathion.

Protocatechuic acid mitigates cadmium-induced neurotoxicity in rats: Role of oxidative stress, inflammation and apoptosis

Environmental and occupational exposure to heavy metals, including cadmium (Cd), is associated with extremely adverse impacts to living systems. Antioxidant agents are suggested to eliminate Cd intoxication. In this paper, we investigated the potential neuroprotective effect of protocatechuic acid (PCA) against Cd-induced neuronal damage in rats. Adult male Wistar rats were randomly divided into control, PCA (100 mg/kg)-treated, CdCl2 (6.5 mg/kg)-treated, and PCA and Cd treatment groups. Pre-treatment with PCA significantly reduced Cd concentrations and increased cortical acetylcholinesterase activity and brain derived neurotrophic factor. Additionally, PCA also prevented CdCl2-induced oxidative stress in the cortical tissue by preventing lipid peroxidation and the formation of nitric oxide (NO), and significantly enhancing antioxidant enzymes. Molecularly, PCA significantly up-regulated the antioxidant gene expression (Sod2, Cat, Gpx1, and Gsr) that was down-regulated by Cd. It should be noted that this effect was achieved by targeting the nuclear-related factor 2 (Nfe2l2) mRNA expression. PCA also prevented the Cd-induced inflammation by reducing the pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β. Moreover, PCA supplementation relieved the Cd-induced neuronal death by increasing Bcl-2 and decreasing Bax and Cas-3 levels in the cortical tissue. The improvement of the cortical tissue histopathology by PCA confirmed the biochemical and molecular data. Collectively, our findings indicate that PCA can counteract Cd-induced cortical toxicity by enhancing the antioxidant defense system and suppressing inflammation and apoptosis.

Red Beetroot Extract Abrogates Chlorpyrifos-Induced Cortical Damage in Rats.

Organophosphorus insecticides including chlorpyrifos (CPF) are mainly used for agriculture, household, and military purposes; their application is associated with various adverse reactions in animals and humans. This study was conducted to evaluate the potential neuroprotective effect of red beetroot methanolic extract (RBR) against CPF-induced cortical damage. Twenty-eight adult male Wistar albino rats were divided into 4 groups (n = 7 in each group): the control group was administered physiological saline (0.9% NaCl), the CPF group was administered CPF (10 mg/kg), the RBR group was administered RBR (300 mg/kg), and the RBR+CPF group was treated with RBR (300 mg/kg) 1 hr before CPF (10 mg/kg) supplementation. All groups were treated for 28 days. Rats exposed to CPF exhibited a significant decrease in cortical acetylcholinesterase activity and brain-derived neurotrophic factor and a decrease in glial fibrillary acidic protein. CPF intoxication increased lipid peroxidation, inducible nitric oxide synthase expression, and nitric oxide production. This was accompanied by a decrease in glutathione content and in the activities of glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase in the cortical tissue. Additionally, CPF enhanced inflammatory response, indicated by increased levels and expression of interleukin-1β and tumor necrosis factor-α. CPF triggered neuronal apoptosis by upregulating Bax and caspase-3 and downregulating Bcl-2. However, RBR reversed the induced neuronal alterations following CPF intoxication. Our findings suggest that RBR can minimize and prevent CPF neurotoxicity through its antioxidant, anti-inflammatory, and antiapoptotic activities.

Atropine counteracts the depressive-like behaviour elicited by acute exposure to commercial chlorpyrifos in rats

Acute organophosphate (OP) poisoning induces well-known signs of toxicosis related to acetylcholinesterase (AChE) inhibition. However, the relationship between acute OP poisoning and the onset of psychiatric disorders remains unclear. Thus, we investigated behavioural and biochemical consequences of acute exposure to the OP chlorpyrifos in male rats and also the effectiveness of the antidotes atropine and pralidoxime on reversing these changes. A sub-lethal dose of commercial chlorpyrifos (20 mg/kg, i.p.) elicited signs of acute toxicosis during the first hours after its injection in rats. Twenty-four hours after treatment, this single dose of chlorpyrifos induced a depressive-like behaviour in the rat forced swimming test without impairing locomotor activity. At this time (24 h), chlorpyrifos decreased plasma butyrylcholinesterase (BChE) activity and hippocampal, striatal and prefrontal cortical AChE activity in rats. The behavioural and biochemical consequences of acute chlorpyrifos poisoning do not seem to be long lasting, since 30 days later they were absent. We evaluated whether these behavioural and biochemical consequences of acute chlorpyrifos treatment would be reversed by the antidotes atropine (10 mg/kg i.p.) and/or pralidoxime (40 mg/kg; i.p.) given 1 h after poisoning. Pralidoxime partially reactivated the AChE activity in the prefrontal cortex, but not in the hippocampus and striatum. Atropine attenuated the depressive-like behaviour induced by chlorpyrifos in rats. Our results suggest that acute chlorpyrifos poisoning induces a transient depressive-like behaviour possible related to hippocampal AChE inhibition. They suggest that treatment with atropine and pralidoxime seems to be insufficient to counteract all the effects of OP acute poisoning, at least in rats.

Novel Tadalafil Derivatives Ameliorates Scopolamine-Induced Cognitive Impairment in Mice via Inhibition of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5).

On the basis of the drug-repositioning and redeveloping strategy, first-generation dual-target inhibitors of acetylcholinesterase (AChE) and phosphodiesterase 5 (PDE5) have been recently reported as a potentially novel therapeutic method for the treatment of Alzheimer's disease (AD), and the lead compound 2 has proven this method was feasible in AD mouse models. In this study, our work focused on exploring alternative novel tadalafil derivatives (3a-s). Among the 19 analogues, compound 3c exhibited good selective dual-target AChE/PDE5 inhibition and good blood-brain barrier (BBB) permeability. Moreover, its citrate (3c·Cit) possessed improved water solubility and good effects against scopolamine-induced cognitive impairment with inhibition of cortical AChE activities and enhancement of cAMP response element-binding protein (CREB) phosphorylation ex vivo.

Voxel-Based Acetylcholinesterase PET Study in Early and Late Onset Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset. The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N-[11C]methylpiperidinyl-4-acetate ([11C]MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age. 22 early onset AD (EOAD) with age at onset under 65, the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [11C]MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p-value <0.05 on cluster-level and cluster extent over 30 voxels. Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann's area 22, Zmax = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart. Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD.

Effect of cholinergic treatment depends on cholinergic integrity in early Alzheimer's disease.

In early Alzheimer's disease, which initially presents with progressive loss of short-term memory, neurodegeneration especially affects cholinergic neurons of the basal forebrain. Pharmacotherapy of Alzheimer's disease therefore often targets the cholinergic system. In contrast, cholinergic pharmacotherapy of mild cognitive impairment is debated since its efficacy to date remains controversial. We here investigated the relationship between cholinergic treatment effects and the integrity of the cholinergic system in mild cognitive impairment due to Alzheimer's disease. Fourteen patients with high likelihood of mild cognitive impairment due to Alzheimer's disease and 16 age-matched cognitively normal adults performed an episodic memory task during functional magnetic resonance imaging under three conditions: (i) without pharmacotherapy; (ii) with placebo; and (iii) with a single dose of rivastigmine (3 mg). Cortical acetylcholinesterase activity was measured using PET with the tracer 11C-N-methyl-4-piperidyl acetate (MP4A). Cortical acetylcholinesterase activity was significantly decreased in patients relative to controls, especially in the lateral temporal lobes. Without pharmacotherapy, mild cognitive impairment was associated with less memory-related neural activation in the fusiform gyrus and impaired deactivation in the posterior cingulate cortex, relative to controls. These differences were attenuated under cholinergic stimulation with rivastigmine: patients showed increased neural activation in the right fusiform gyrus but enhanced deactivation of the posterior cingulate cortex under rivastigmine, compared to placebo. Conversely, controls showed reduced activation of the fusiform gyrus and reduced deactivation of the posterior cingulate under rivastigmine, compared to placebo. In both groups, the change in neural activation in response to rivastigmine was negatively associated with local acetylcholinesterase activity. At the behavioural level, an analysis of covariance revealed a significant group × treatment interaction in episodic memory performance when accounting for hippocampal grey matter atrophy and function. Our results indicate that rivastigmine differentially affects memory-related neural activity in patients with mild cognitive impairment and cognitively normal, age-matched adults, depending on acetylcholinesterase activity as a marker for the integrity of the cortical cholinergic system. Furthermore, hippocampal integrity showed an independent association with the response of memory performance to acetylcholinesterase inhibition.

Effect of khat extract on young rat's memory

Consumption of khat is still pressing issue in Jazan region. The present study was imperative to know the effect of khat use on memory of young rats. The current study used rats in age comparable to adult humans that mimic the stages of education and grouped in four groups. 1-control normal, 2-scopolamine, 3-khat extract administered group for four weeks, 4- khat withdrawal group administered khat extract for four weeks then left for one week without khat administration. All groups of rats were trained using Morris water maze task before treatment then the behavioral test was performed after treatments and cortex acetylcholinesterase (AChE) enzyme activities were determined in all groups. The body weights were detected weekly. The study showed that khat extract impaired performance in the water maze test, increased cortical AChE activity and reduced the body weight in a time related manner, meanwhile khat withdrawals showed partial retention of the maze performance, reduction in AChE activity and body weight gain. The study knocks alarm on cognitive impairment due to khat consumption especially on youth.

Cholinesterase Inhibitor Therapy in Alzheimer's Disease: The Limits and Tolerability of Irreversible CNS-Selective Acetylcholinesterase Inhibition in Primates.

Irreversible acetylcholinesterase (AChE) inhibition accumulates to high levels in the central nervous system (CNS) because AChE turnover in the brain is much slower than in peripheral tissues. As expected from this CNS selectivity, the irreversible AChE inhibitor methanesulfonyl fluoride (MSF) produces significant cognitive improvement in Alzheimer's disease patients without the gastrointestinal toxicity that plagues other AChE inhibitors. However, without dose-limiting gastrointestinal toxicity, one shortcoming of the prior human studies of MSF is that the upper limits of CNS AChE inhibition that might be tolerated could not be tested. Therefore, in this study, monkeys were treated with escalating intramuscular (IM) doses of MSF that culminated with several weeks of 1.5 mg/kg dosing, more than eight times the prior human clinical dose, still without signs of toxicity. Brain biopsies showed that ∼80% AChE inhibition had been produced and that the new synthesis of cortical AChE had a half-time (t1/2) of ∼12 days. A single IM dose of 1.5 mg/kg MSF produced ∼59% inhibition in cerebrospinal fluid (CSF) AChE as measured one day later. This corresponds to a peak of ∼80% inhibition in CSF AChE at the time of the injection, recovering with a t1/2 of 2.4 days. Computational analyses suggest that MSF at clinically relevant doses could theoretically produce a steady-state AChE inhibition between 65% and 85% in the CNS. These data suggest that the full therapeutic advantage of AChE inhibition therapy can be realized without interference from dose-limiting gastrointestinal toxicity if an irreversible inhibitor is employed.

Effect of canagliflozin and metformin on cortical neurotransmitters in a diabetic rat model

BackgroundThe rapid economic development in the Arabian Gulf has resulted in lifestyle changes that have increased the prevalence of obesity and type 2 diabetes, with the greatest increases observed in Kuwait. Dyslipidemia and diabetes are risk factors for disruptions in cortical neurotransmitter homeostasis. This study investigated the effect of the antidiabetic medications canagliflozin (CAN) and metformin (MET) on the levels of cortical neurotransmitters in a diabetic rat model. Materials and methodsThe rats were assigned to the control (C) group, the diabetic group that did not receive treatment (D) or the diabetic group treated with either CAN (10 mg/kg) or MET (100 mg/kg) for 2 or 4 weeks. Blood and urine glucose levels and cortical acetylcholinesterase (AChE) activity were assayed, and amino acid and monoamine levels were measured using HPLC. ResultsThe diabetic group exhibited a significant increase in AChE activity and a decrease in monoamine and amino acid neurotransmitter levels. In the CAN group, AChE was significantly lower than that in the D and D + MET groups after 2 weeks of treatment. In addition, a significant increase in some cortical monoamines and amino acids was observed in the D + MET and D + CAN groups compared with the D group. Histopathological analysis revealed the presence of severe focal hemorrhage, neuronal degeneration, and cerebral blood vessel congestion, with gliosis in the cerebrum of rats in the D group. The CAN-treated group exhibited severe cerebral blood vessel congestion after 2 weeks of treatment and focal gliosis in the cerebrum after 4 weeks of treatment. Focal gliosis in the cerebrum of rats in the MET-treated group was observed after 2 and 4 weeks of treatment. ConclusionsWe conclude that the effect of CAN and MET on neurotransmitters is potentially mediated by their antihyperglycemic and antihyperlipidemic effects. In addition, the effects of CAN on neurotransmitters might be associated with its receptor activity, and the effect of MET on neurotransmitters might be associated with cerebral metabolism.