Antisense inhibition of acetylcholinesterase gene expression for treating cognition deficit in Alzheimer's disease model mice

To examine whether the selected antisense oligodeoxynucleotides (AS-ODN) targeting against human brain acetylcholinesterase (AChE) mRNA could improve the cognitive deficit in the Alzheimer's disease (AD) model mice induced by amyloid-beta peptide (Abeta), we determined the time-effect relationship of AChE activity and the learning and memory after AS-ODN delivery. The results showed that the AChE activity decreased gradually along with time, initiating at 8 h and lasting 42 h. The time-effect curves of acetylcholine (ACh) behaved consistency with that of AChE activity. The animal cognition studies showed that in step-through test, the error number of the AS-ODN-treated AD model mice was significantly decreased, and the memory retention was increased. In the water maze performance, the swimming time obviously shortened. Our results indicated that antisense therapy is of potential use in the treatment of cognitive deficit in the Abeta model mice.     

A correlation between regional acetylcholinesterase activity in rat brain and performance in a spatial task

The acquisition and retention of a water maze task was examined in 12 intact, young Wistar rats. Acetylcholinesterase activity in 43 discrete brain regions was then measured in the same rats by quantitative histochemistry. Individual learning and retention indices were found to be significantly correlated with acetylcholinesterase (AChE) levels in specific regions, e.g. cholinergic nuclei; the ventral pallidum and nucleus basalis; and in the dentate gyrus of the hippocampus. High levels of AChE in these regions predicted poor performance in the water maze. Thus cholinergic activity in selected regions of the rat brain might be involved in the performance of spatial memory tasks.     

Coenzyme Q10 modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats

Coenzyme Q10 (CoQ10), a peculiar lipophilic antioxidant, is an essential component of the mitochondrial electron-transport chain. It is involved in the manufacturing of adenosine triphosphate (ATP) and has been linked with improving cognitive functions. The present study shows the neuroprotective effect of CoQ10 on cognitive impairments and oxidative damage in hippocampus and cerebral cortex of intracerebroventricular-streptozotocin (ICV-STZ) infused rats. Male Wistar rats (1-year old) were infused bilaterally with an ICV injection of STZ (1.5 mg/kg b.wt., in normal saline), while sham group received vehicle only. After 24 h, the rats were supplemented with CoQ10 (10 mg/kg b.wt. i.p.) for 3 weeks. The learning and memory tests were monitored 2 weeks after the lesioning. STZ-infused rats showed the loss of cognitive performance in Morris water maze and passive avoidance tests. Three weeks after the lesioning, the rats were sacrificed for estimating the contents of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), protein carbonyl (PC), ATP and the activities of glutathione peroxidase (GPx), glutathione reductase (GR), cholineacetyltransferase (ChAT) and acetylcholinesterase (AChE). Significant alteration in the markers of oxidative damage (TBARS, GSH, PC, GPx and GR) and a decline in the level of ATP were observed in the hippocampus and cerebral cortex of ICV-STZ rat. A significant decrease in ChAT activity and a concomitant increase in AChE activity were observed in the hippocampus. However, supplementation with CoQ10 in STZ-infused rats reversed all the parameters significantly. Thus, the study demonstrates that CoQ10 may have a therapeutic importance in the treatment of Alzheimer's type dementia.     

Aluminum Exposure at Human Dietary Levels for 60 Days Reaches a Threshold Sufficient to Promote Memory Impairment in Rats

Aluminum (Al) is a significant environmental contaminant. While a good deal of research has been conducted on the acute neurotoxic effects of Al, little is known about the effects of longer-term exposure at human dietary Al levels. Therefore, the purpose of this study was to investigate the effects of 60-day Al exposure at low doses for comparison with a model of exposure known to produce neurotoxicity in rats. Three-month-old male Wistar rats were divided into two major groups: (1) low aluminum levels, and (2) a high aluminum level. Group 1 rats were treated orally by drinking water for 60 days as follows: (a) control—received ultrapure drinking water; (b) aluminum at 1.5 mg/kg b.w., and (c) aluminum at 8.3 mg/kg b.w. Group 2 rats were treated through oral gavages for 42 days as follows: (a) control—received ultrapure water; (b) aluminum at 100 mg/kg b.w. We analyzed cognitive parameters, biomarkers of oxidative stress and acetylcholinesterase (AChE) activity in hippocampus and prefrontal cortex. Al treatment even at low doses promoted recognition memory impairment seen in object recognition memory testing. Moreover, Al increased hippocampal reactive oxygen species and lipid peroxidation, reduced antioxidant capacity, and decreased AChE activity. Our data demonstrate that 60-day subchronic exposure to low doses of Al from feed and added to the water, which reflect human dietary Al intake, reaches a threshold sufficient to promote memory impairment and neurotoxicity. The elevation of oxidative stress and cholinergic dysfunction highlight pathways of toxic actions for this metal.     

Rutin restores neurobehavioral deficits via alterations in cadmium bioavailability in the brain of rats exposed to cadmium

Many plant foods are rich sources of rutin, a flavonoid with many biological activities and health benefits. Exposure to cadmium has been implicated in neurotoxicity and cognitive dysfunction in animal models. However, there is a dearth of information on the effect of rutin on the cadmium bioavailability in the brain of rats exposed to cadmium. Thus, the present study investigated the therapeutic efficacy of rutin in an animal model of cognitive impairment via alterations of cadmium bioavailability in cadmium-exposed rats. Animals were divided into six groups (n = 6): group 1 served as control, groups 2 and 3 are normal rats received 25 and 50 mg/kg of rutin respectively, group 4 received cadmium (5 mg/kg), while groups 5 and 6 are cadmium-exposed rats treated with 25 and 50 mg/kg rutin respectively via oral administration for 21 days. Rutin was administered 30 min after cadmium administration each day. The spatial working memory of the exposed and treated rats was assessed using Morris water maze and Y-Maze tasks. Furthermore, the residual level of cadmium ion in the brain of the rats was estimated. The cholinesterase (AChE and BChE) activities and nitric oxide level were determined. Besides, the level of oxidative stress markers (ROS and MDA) was assessed. Results revealed that rutin significantly reduced cadmium bioavailability in the brain of cadmium-exposed rats. Moreso, cadmium increased cholinesterase (AChE and BChE) activities and level of oxidative stress markers in the brain, with a concomitant decrease in nitric oxide level. However, treatment with rutin decreased cholinesterase activities and the level of oxidative stress markers in cadmium-exposed rats. Also, rutin improved spatial working memory and learning processes as revealed by Morris water maze and Y-Maze tasks. Conclusively, rutin could be considered to possess cognitive-enhancing properties possibly through alterations of cadmium bioavailability in the brain of cadmium-exposed rats.     

Memory improvement by modafinil at cost of metabolic hazards? A study to decipher the benefits and risks of modafinil in rats

BackgroundModafinil is approved for narcolepsy and achieved high success in off-label indications in memory-related disorders. However, chronic indiscriminate use of modafinil imposes several health hazards like hyperglycaemia, obesity and metabolic syndrome, owing to impairment of sleep-wake cycle, circadian-rhythm, and neurotransmission. The present protocol elucidates the effects of modafinil per se and diabetic complications apropos.MethodsModafinil (100 and 200 mg/kg) was administered in rats from day 5–26. To induce type-2 diabetes, streptozotocin (STZ) was given on day 1, and blood glucose assessed on day 5. CPP (combination propranolol and phentolamine) was administered to antagonize sympathetic activity. After evaluation of cognitive functions, serum lipid profile, and biomarkers of oxidative stress and acetylcholinesterase (AChE) activity were assessed.ResultsSubacute dosing of modafinil significantly elevated blood glucose levels, albeit considerably less than diabetic group, and attenuated brain oxidative stress and AChE activity. Modafinil caused significant dyslipidaemia, increased body weight, whereas modestly altered abdominal circumference (AC) and thoracic circumference (TC) in rats. Significant hyperglycaemia, derangement of serum lipid-profile, brain lipid peroxidation, cholinergic hypofunction, and decrease in body weight and ACTC was noted in diabetic rats. Modafinil (100 mg/kg) significantly potentiated the hyperglycaemia and dyslipidaemia, however, attenuated oxidative stress and AChE activity in diabetic rats. Modafinil increased short-term (working) memory but not long-term spatial memory in normal and diabetic rats. CPP infusion attenuated these effects of modafinil.ConclusionSubacute dosing of modafinil differentially modulates long-term and short-term memory subtypes, and also predisposes towards metabolic derangements.     

Cholinesterases in the cerebrospinal fluid,plasma, and erythrocytes of patients with Alzheimer's disease

Summary In patients with probable Alzheimer's disease and in controls, acetyl- and butyrylcholinesterase activities were studied in cerebrospinal fluid (CSF) and plasma, and acetylcholinesterase activity of erythrocytes was determined. In addition, the molecular forms of acetylcholinesterase were measured in CSF. Severely demented patients had significantly lower acetylcholinesterase (p<0.01) and butyrylcholinesterase (p<0.05) activities in CSF than the controls had, but the activities of these enzymes in plasma and erythrocytes were within the same range in both groups. Acetylcholinesterase and butyrylcholinesterase activities in the CSF of mildly demented patients did not differ from control values. The ratio of the intermediate molecular form of acetylcholinesterase to the light molecular form of the enzyme did not differ significantly between patients with Alzheimer's disease and controls. According to our results, AChE levels were lower in the CSF of severely demented patients, but both light and intermediate molecular forms were affected.     

Developmental lead neurotoxicity: alterations in brain cholinergic system

Developing brain has been shown to be susceptible to the neurotoxic effects of lead (Pb). Our earlier studies (Reddy GR, Riyaz Basha Md, Devi CB, Suresh A, Baker JL, Shafeek A, Heinz J, Chetty CS. Lead induced effects on acetylcholinesterase activity in cerebellum and hippocampus of developing rat. Int J Devl Neurosci 2003;21:347-52) have shown decrease in acetylcholinesterase (AChE) activity in the crude homogenates of cerebellum and hippocampus of rat brain exposed to Pb. In this study, we have further examined in detail, the alterations in AChE activity and acetylcholine (ACh) levels in different brain regions using histochemical and spectrophotometric methods. Rats were lactationally exposed to low level (0.2%) and high level (1%) Pb. The studies were conducted in young (1 month) and adult (3 months) rats. Pb exposure significantly decreased the specific activity of AChE and increased the levels of ACh in the synaptosomal fractions of cerebellum, hippocampus and cerebral cortex in a dose- and age-dependent manner. These alterations in AChE and ACh were more predominant in young rat brain as compared to adult brain. Maximum AChE activity and ACh level as well as maximum alterations following Pb exposure were observed in synaptosomes of hippocampus. Histochemical studies also showed higher AChE activity in the hippocampal region compared to other areas of brain as revealed by the intensity of AChE staining. Though high level Pb exposure remarkably decreased the intensity of AChE staining in the dentate gyrus, CA2 and CA3 areas of hippocampus, and different cell layers of cortex and cerebellum, highly significant loss of AChE activity was observed in the CA3 region of hippocampus, molecular layer of cerebellum and cortical cell layers. These data suggest that Pb exposure may selectively affect cholinergic system in brain areas controlling learning and cognitive behavior.     

Mitochondrial involvement in memory impairment induced by scopolamine in rats

Objective: Scopolamine (SCO) administration to rats induces molecular features of AD and other dementias, including impaired cognition, increased oxidative stress, and imbalanced cholinergic transmission. Although mitochondrial dysfunction is involved in different types of dementias, its role in cognitive impairment induced by SCO has not been well elucidated. The aim of this work was to evaluate the in vivo effect of SCO on different brain mitochondrial parameters in rats to explore its neurotoxic mechanisms of action.

Methods: Saline (Control) or SCO (1 mg/kg) was administered intraperitoneally 30 min prior to neurobehavioral and biochemical evaluations. Novel object recognition and Y-maze paradigms were used to evaluate the impact on memory, while redox profiles in different brain regions and the acetylcholinesterase (AChE) activity of the whole brain were assessed to elucidate the amnesic mechanism of SCO. Finally, the effects of SCO on brain mitochondria were evaluated both ex vivo and in vitro, the latter to determine whether SCO could directly interfere with mitochondrial function.

Results: SCO administration induced memory deficit, increased oxidative stress, and increased AChE activities in the hippocampus and prefrontal cortex. Isolated brain mitochondria from rats administered with SCO were more vulnerable to mitochondrial swelling, membrane potential dissipation, H₂O₂ generation and calcium efflux, all likely resulting from oxidative damage. The in vitro mitochondrial assays suggest that SCO did not affect the organelle function directly.

Conclusion: In conclusion, the present results indicate that SCO induced cognitive dysfunction and oxidative stress may involve brain mitochondrial impairment, an important target for new neuroprotective compounds against AD and other dementias.     

Cholinergic projections from magnocellular nuclei of the basal forebrain to cortical areas in rats

Acetylcholinesterase (AChE) and choline acetyltransferase (ChAc) activities were studied by quantitative histochemical (AChE) as well as biochemical methods (AChE, ChAc) in certain cortical brain areas in rats after stereotaxic lesions had been placed in several structures of the basal forebrain. After lesioning the magnocellular nuclei of the substantia innominata (nuc. basalis Meynert, NBM) the activities of AChE and ChAc decreased to moderate or low residual values in the ipsilateral cortical areas. This indicated that cholinergic pathways were directly linked to frontal, sensory-motor, auditory and visual cortex. After lesions of the globus pallidus the decrease in cortical AChE activity was less pronounced. Lesions of the caudate, accumbens or entopeduncular nucleus did not influence the cortical AChE activities.The results are discussed with respect to the similarity of the organization of the cholinergic projection to the cortex arising from NBM cells and the monoaminergic system which innervates the cortex. It is suggested that both neurotransmitter systems by their interaction might modulate and control cortical information processing and behavior in a manner analogous to the control of peripheral activity by the sympathetic and parasympathetic system.     

Effect of donepezil on brain acetylcholinesterase activity in patients with AD measured by PET

Acetylcholinesterase (AChE) activities in the brain of three patients with AD were measured once before and once during donepezil treatment (5 mg/d in two patients, 3 mg/d in one patient) using PET and N-[11C]methylpiperidin-4-yl acetate. Donepezil reduced k(3) values, an index of AChE activity, in the cerebral cortex by 39 +/- 5%. All patients showed some degree of symptomatic improvement, and it was concluded that this improvement was likely caused by improved cholinergic activity by inhibition of AChE in the brain.     

Acetylcholinesterase inhibition in the basolateral amygdala plays a key role in the induction of status epilepticus after soman exposure

Exposure to nerve agents induces intense seizures (status epilepticus, SE), which cause brain damage or death. Identification of the brain regions that are critical for seizure initiation after nerve agent exposure, along with knowledge of the physiology of these regions, can facilitate the development of pretreatments and treatments that will successfully prevent or limit the development of seizures and brain damage. It is well-established that seizure initiation is due to excessive cholinergic activity triggered by the nerve agent-induced irreversible inhibition of acetylcholinesterase (AChE). Therefore, the reason that when animals are exposed to lethal doses of a nerve agent, a small proportion of these animals do not develop seizures, may have to do with failure of the nerve agent to inhibit AChE in brain areas that play a key role in seizure initiation and propagation. In the present study, we compared AChE activity in the basolateral amygdala (BLA), hippocampus, and piriform cortex of rats that developed SE (SE rats) after administration of the nerve agent soman (154 μg/kg) to AChE activity in these brain regions of rats that received the same dose of soman but did not develop SE (no-SE rats). The levels of AChE activity were measured at the onset of SE in SE rats, 30 min after soman administration in no-SE rats, as well as in controls which received saline in place of soman. In the control group, AChE activity was significantly higher in the BLA compared to the hippocampus and piriform cortex. Compared to controls, AChE activity was dramatically lower in the hippocampus and the piriform cortex of both the SE rats and the no-SE rats, but AChE activity in the BLA was reduced only in the SE rats. Consistent with the notion that soman-induced neuropathology is due to intense seizures, rather than due to a direct neurotoxic effect of soman, no-SE rats did not present any neuronal loss or degeneration, 7 days after exposure. The results suggest that inhibition of AChE activity in the BLA is necessary for the generation of seizures after nerve agent exposure, and provide strong support to the view that the amygdala is a key brain region for the induction of seizures by nerve agents.     

Acetylcholinesterase and butyrylcholinesterase activity in the cerebrospinal fluid of patients with neurodegenerative diseases involving cholinergic systems.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were assayed in the cerebrospinal fluid (CSF) of subjects with neurodegenerative diseases (dementing and non-dementing, with and without known cholinergic lesions), to determine whether CSF AChE is a valid marker of central cholinergic activity. The relative proportions of the different forms of each enzyme and of AChE to BChE were similar in CSF and brain. AChE decreased in Huntington's chorea (degeneration of striatal cholinergic interneurons) but also in multiple sclerosis (not known to affect cholinergic systems). BChE paralleled AChE, although the enzymes were dissociated in some patients. It is concluded that CSF AChE activity may globally reflect brain AChE, but pathology-induced changes may not be directly reflected.     

Pharmacological characterization of orally active cholinesterase inhibitory activity of Prunus persica L. Batsch in rats

Prunus persica L. Batsch water extract (PPE) is a potent acetylcholinesterase (AChE) inhibitor screened for the treatment of Alzheimer's disease. The effects of oral administration of the PPE were examined with comparison of those of selective butyrylcholinesterase inhibitors of 9-amino-1,2,3,4-tetrahydroacridine hydrochloride (tacrine) and tetraidopropylpyrophosphoramide (iso-OMPA) and a selective AChE inhibitor, donepezil, on the cholinesterase activity in the brain and plasma of rats. After the sequential solvent fractionation of the methanol extract of P. persica L. Batsch, the highest inhibitory fraction was that of chloroform (75%). The concentration that was required for 50% enzyme inhibition (IC₅₀ value) was 5.6 μg/mL. for the chloroform fraction. Oral administration of PPE or tacrine caused a dose-dependent inhibition of brain and plasma cholinesterase activities. The ID₅₀ values of these compounds for brain cholinesterase activity were 2.7 g/kg and 8.9 mg/kg, respectively. On the other hand, the ID₅₀ values for plasma cholinesterase activity were 18.6 g/kg and 27.5 mg/kg, respectively. Thus, the ratios of the ID₅₀ (plasma<brain) were 6.0 and 3.1, respectively. These results suggest that orally administered PPE satisfactorily penetrates into the brain and inhibits cholinesterase there and that PPE is a potent inhibitor of brain cholinesterase in comparison with plasma cholinesterase in vivo.     

Effect of Prenatal Hypoxia on Cholinesterase Activity in Blood Serum of Rats

Analysis of acetylcholine- and butyrylcholinesterase (AChE, BChE) in blood serum of rats of different ages demonstrated that their activities significantly decrease during ageing. Moreover, in mature rats (5 and 8 months) subjected to prenatal hypoxia during the period of active formation of the brain (E14, 7% O₂, 3 h) there was a two-fold decrease in the activity both of AChE and BChE. Prenatal hypoxia at a later stage of pregnancy (E18) also resulted in decreased activity of BChE in the blood serum of mature rats while AChE activity was significantly higher than in controls. Levels of cholinesterase activity in blood serum also correlated with the motor activity of rats. In active mature rats, AChE activity was, on average, 10% higher and BChE, 21% higher than in passive rats. Administration of a natural antioxidant L-carnitine or a synthetic tyrosine kinase inhibitor imatinib (gleevec) to animals resulted in an increase in the activity of both cholinesterases in the serum. The data obtained testify not only on the prolonged effects of prenatal stress on the cholinergic brain system reported by us earlier but also on the activities of AChE and BChE in blood serum which might affect not only motor and cognitive functions of animals but also their reactions to different types of stress.     

Lead induced effects on acetylcholinesterase activity in cerebellum and hippocampus of developing rat

Exposure to low-levels of lead (Pb) during early development has been implicated in behavioral abnormalities and cognitive deficits in children. The present study is focused on developmental changes in hippocampus and cerebellum of rats following perinatal exposure to Pb. Pregnant rats were exposed to 0.2% Pb-acetate from gestation day 6 (GD 6) through postnatal day (PND) 21 and the activity levels of acetylcholinesterase (AChE) were estimated in cerebellum and hippocampus of pups at specific time points for 5 weeks. In both the brain regions, Pb-exposure decreased AChE activity with an increase in age. Histochemical observations conducted in 35 days old rat brain showed decreased AChE activity conspicuously in stratum oriens and dentate gyrus of hippocampus, and molecular and granule cell layers of cerebellum. In vitro studies conducted in 35 days old rat brain showed a considerable decrease in the specific activity of AChE at high concentrations (50-100 microM) of Pb in a concentration-dependent manner. However, at low concentrations (5-20 microM), Pb failed to produce such changes. In the presence of eserine (physostigmine), the specific inhibitor of AChE, the inhibitory effect of Pb was potentiated and this was more pronounced at low-concentrations of Pb. The behavioral responses in open-field also showed a significant decrease in both Pb exposed as well as eserine administered rats. These data suggest that low-level perinatal Pb-exposure induces alterations in cholinergic system in the cerebellum and hippocampus of developing brain even after the withdrawal of Pb-exposure, that may contribute to behavioral and learning deficits.     

Changes in Learning and Memory, Acetylcholinesterase Activity and Monoamines in Brain After Chronic Carbamazepine Administration in Rats

Summary Groups of adult male Wistar rats were administered carbamazepine (CBZ) in doses of 5, 10, 20, 40, or 80 mg/kg/day intraperitoneally (i.p.) for 21 days. The learning and memory of the rats were assessed by the T-maze and passive avoidance tests. The CBZ plasma levels, the activity of acetylcholinesterase (AChE) in different brain regions, and the levels of monoamines in the hippocampus were also measured. None of the administered doses of CBZ impaired learning and memory. Rats with CBZ plasma levels of 2.5 and 4.5 μg/ml corresponding to the doses of 20 and 40 mg/kg, learned significantly better than controls. AChE activity was decreased in hippocampus and pyriform cortex (19%) in these groups. Simultaneously, an increase in the serotonin (5-HT) (36%) and dopamine (137%) levels in the hippocampus was noted in the 20-mg/kg CBZ group. 5–Hydroxyindole acetic acid (5-HIAA) and homovanillic acid (HVA) levels were increased at 10-, 20-, and 40-mg/kg CBZ doses. However, a dose of 80-mg/kg caused no change in learning performance as compared with that of controls. Correspondingly, no changes were evident in the AChE activity or monoamine levels. We postulated that the decreased AChE activity caused by CBZ in the therapeutic range may lead to increased ACh levels in brain, thus producing improvement in learning and memory. The increased turnover of 5-HT and dopamine (DA) in the hippocampus may play a role in long-term potentiation and improvement in memory.     

Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by rivastigmine: correlation with cognitive benefit

Cholinesterase (ChE) inhibition represents the most efficacious treatment approach for Alzheimer's disease (AD) to date. This multiple-dose study has examined the relationship between inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities in the cerebrospinal fluid (CSF) and cognitive change (measured by the Computerised Neuropsychological Test Battery [CNTB]) following administration of the ChE inhibitor, rivastigmine (Exelon). In 18 patients with mild to moderate AD, CNTB scores, activities of AChE and BuChE in the CSF, and plasma BuChE activity were determined prior to treatment with rivastigmine. Doses of rivastigmine were then titrated (1 mg b.i.d./week) to final doses of 1, 2, 3, 4, 5 or 6 mg b.i.d. (n = 3 per dose). Following treatment with the target dose of rivastigmine for at least 3 days, CNTB scores were re-determined. CSF samples were continuously collected together with plasma samples prior to and for 12 hours after the final dose of rivastigmine, and AChE and BuChE activities determined.AChE in CSF and BuChE in plasma were dose-dependently inhibited by rivastigmine treatment. The inhibition of BuChE in CSF was not clearly dose-dependent. A statistically significant correlation was observed between the change in CNTB summary score and inhibition of AChE activity (r = -0.56, p < 0.05) and BuChE activity (r = -0.65, p < 0.01) in CSF. Improvement in speed-, attention- and memory-related subtests of the CNTB correlated significantly with inhibition of BuChE but not AChE activity in CSF. Weak or absent correlation with change in cognitive performance was noted for inhibition of plasma BuChE. These results indicate that cognitive improvement with rivastigmine in AD is associated with central inhibition of ChEs and support a role for central BuChE in addition to AChE inhibition in modulating cholinergic function in AD.     

Ectonucleotidase and acetylcholinesterase activities in synaptosomes from the cerebral cortex of streptozotocin-induced diabetic rats and treated with resveratrol

The aim of the present study was to investigate the effects of resveratrol (RV), an important neuroprotective compound on NTPDase, 5′-nucleotidase and acetylcholinesterase (AChE) activities in cerebral cortex synaptosomes of streptozotocin (STZ)-induced diabetic rats. The animals were divided into six groups (n = 8): control/saline; control/RV 10 mg/kg; control/RV 20 mg/kg; diabetic/saline; diabetic/RV 10 mg/kg; diabetic/RV 20 mg/kg. After 30 days of treatment with resveratrol the animals were sacrificed and the cerebral cortex was removed for synaptosomes preparation and enzymatic assays. The results demonstrated that NTPDase and 5′-nucleotidase activities were significantly increased in the diabetic/saline group (p < 0.05) compared to control/saline group. Treatment with resveratrol significantly increased NTPDase, 5′-nucleotidase activities in the diabetic/RV10 and diabetic/RV20 groups (p < 0.05) compared to diabetic/saline group. When resveratrol was administered per se there was also an increase in the activities of these enzymes in the control/RV10 and control/RV20 groups (p < 0.05) compared to control/saline group. AChE activity was significantly increased in the diabetic/saline group (p < 0.05) compared to control/saline group. The treatment with resveratrol prevented this increase in the diabetic/RV10 and diabetic/RV20 groups. In conclusion, this study demonstrated that the resveratrol interfere with the purinergic and cholinergic neurotransmission by altering NTPDase, 5′-nucleotidase and AChE activities in cerebral cortex synaptosomes of diabetic rats. In this context, we can suggest that resveratrol should be considered potential therapeutics and scientific tools to be investigated in brain disorders associated with the diabetes.