ABSTRACT
Diabetic neuropathy is considered as a disease of the peripheral nervous system, but recent evidences suggest the involvement of central nervous system as well. In this study we evaluated the effect of Urtica dioica (UD) extract against memory dysfunction and hypoalgesia on a mouse model of streptozotocin (STZ) induced diabetic neuropathy. STZ (50 mg/kg, i.p. consecutively for 5 days) was used to induce diabetes, followed by treatment with the UD extract (50 mg/kg, oral) and rosiglitazone (5 mg/kg, oral) for 8 weeks. Cognitive functions were evaluated using Morris water maze and passive avoidance step through task. Pain thresholds were measured using thermal, mechanical and chemical induced hyperalgesia. We observed that chronic diabetes resulted in a decline in circulating insulin level, elevated blood glucose, reduced body weight, increased water intake, cognitive impairment and hypoalgesia. UD significantly reduced the blood glucose and polydypsia, as well as improved the body weight, insulin level, cognition and insensate neuropathy. In conclusion, UD showed results comparable to rosiglitazone in reversing the long standing diabetes induced complications such as central and peripheral neuronal dysfunction.
Subject(s)
Diabetic Neuropathies/drug therapy , Memory Disorders/drug therapy , Pain Threshold/drug effects , Phytotherapy , Plant Extracts/therapeutic use , Urtica dioica , Animals , Avoidance Learning/drug effects , Blood Glucose/drug effects , Body Weight/drug effects , Diabetic Neuropathies/chemically induced , Diabetic Neuropathies/complications , Drug Therapy, Combination , Insulin/blood , Maze Learning/drug effects , Memory Disorders/complications , Mice , Plant Extracts/administration & dosage , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Leaves/chemistry , Polydipsia/complications , Polydipsia/drug therapy , Rosiglitazone , Streptozocin , Thiazolidinediones/administration & dosage , Thiazolidinediones/therapeutic useABSTRACT
The deregulation of cholinergic system and associated neuronal damage is thought to be a major contributor to the pathophysiologic sequelae of hypobaric hypoxia-induced memory impairment. Uniquely, the muscarinic receptors also play a role in zinc uptake. Despite the potential role of muscarinic receptors in the development of post hypoxia cognitive deficits, no studies to date have evaluated the mechanistic relationship between memory dysfunction and zinc homeostasis in brain. In the present study, we evaluated the effect of Ca(2)EDTA, a specific zinc chelator in the spatial working and associative memory deficits following hypobaric hypoxia. Our results demonstrate that accumulation of intracellular free chelatable zinc in the hippocampal CA3 pyramidal neurons is accompanied with neuronal loss and memory impairment in hypobaric hypoxic condition. Chelation of this free zinc with Ca(2)EDTA (1.25 mM/kg) ameliorated the hippocampus-dependent spatial as well as associative memory dysfunction and neuronal damage observed on exposure to hypobaric hypoxia. The zinc chelator significantly alleviated the downregulation in expression of choline acetyltransferase, muscarinic receptor 1 and 4, and acetylcholinesterase activity due to hypobaric hypoxia. Our data suggest that the free chelatable zinc released during hypobaric hypoxia might play a critical role in the neuronal damage and the alteration in cholinergic function associated with hypobaric hypoxia-induced memory impairment. We speculate that zinc chelation might be a potential therapy for hypobaric hypoxia-induced cognitive impairment.
Subject(s)
Chelating Agents/pharmacology , Hypoxia/pathology , Neurons/pathology , Parasympathetic Nervous System/physiology , Zinc/physiology , Acetylcholinesterase/metabolism , Air Pressure , Animals , Association Learning/physiology , CA3 Region, Hippocampal/chemistry , CA3 Region, Hippocampal/metabolism , Comet Assay , Dose-Response Relationship, Drug , Edetic Acid/pharmacology , Fluorescent Antibody Technique , Hippocampus/cytology , Hippocampus/metabolism , Hippocampus/pathology , L-Lactate Dehydrogenase/metabolism , Male , Maze Learning/physiology , Memory, Short-Term/physiology , Mice , Mice, Inbred BALB C , RNA/biosynthesis , RNA/isolation & purification , Receptor, Muscarinic M1/metabolism , Receptor, Muscarinic M4/metabolism , Zinc/bloodABSTRACT
Forebrain cholinergic dysfunction is the hallmark of vascular dementia (VaD) and Alzheimer's dementia (AD) induced by cerebral hypoperfusion during aging. The aim of the present study is to evaluate the role of angiotensin converting enzyme (ACE) in cerebral hypoperfusion-induced dementia and cholinergic dysfunction. Chronic cerebral hypoperfusion (CHP) was induced by permanent bilateral common carotid artery (2VO) occlusion in rats. Chronic cerebral hypoperfusion resulted in anterograde memory impairment revealed from Morris water maze (MWM) and passive avoidance step through tasks (PA), which was significantly attenuated by ACE inhibitor, captopril. Cerebral hypoperfusion down-regulated the relative expression of cholinergic muscarinic receptor (ChM-1r) and choline acetyltransferase (ChAT) as well as up-regulated the angiotensin II type-1 receptor (AT-1) expression in hippocampus of vehicle treated CHP group on the 54th day post-hypoperfusion. The diminished number of presynaptic cholinergic neurons and the pyramidal neurons were evident from ChAT-immunofluorescence and the hematoxylin and eosin (H&E) staining studies respectively in hippocampal Cornu ammonis1 (CA1); region of vehicle-treated hypoperfused animals. Further the lipid peroxidation level was also found to be elevated in the hippocampus of the vehicle-treated group. Our results demonstrated that continuous captopril treatment (50 mg/kg, i.p. twice daily) for 15 days mitigated the hypoperfusion-induced cholinergic hypofunction and neurodegeneration in hippocampus. The present study robustly reveals that the angiotensinergic system plays a pivotal role in progression of neuronal death and memory dysfunctions during cerebral hypoperfusion.
Subject(s)
Acetylcholine/metabolism , Amnesia, Anterograde/etiology , Amnesia, Anterograde/metabolism , Infarction, Middle Cerebral Artery/complications , Peptidyl-Dipeptidase A/metabolism , Amnesia, Anterograde/pathology , Analysis of Variance , Animals , Avoidance Learning/drug effects , Avoidance Learning/physiology , Behavior, Animal , Captopril/pharmacology , Cholinesterases/metabolism , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Hippocampus/drug effects , Hippocampus/metabolism , Lipid Peroxidation/drug effects , Lipid Peroxidation/physiology , Male , Malondialdehyde/metabolism , Maze Learning/drug effects , Maze Learning/physiology , Peptidyl-Dipeptidase A/genetics , Rats , Rats, Sprague-Dawley , Reaction Time/drug effects , Reaction Time/physiology , Time FactorsABSTRACT
The mechanisms responsible for cholinergic dysfunction associated learning and memory impairment during hypoxia are not well-understood. However it is known that inflammatory mediators like inducible nitric oxide synthase (iNOS) hamper the functions of cholinergic neurons. In this present experiment we made an effort to study the iNOS expression mediated retrograde and anterograde memory impairment in Balb/c mice following acute hypobaric hypoxia (at an altitude of 23,000ft for 6h) using elevated plus maze and passive avoidance step-through tasks. Our results demonstrated that hypoxia transiently impairs the retrograde memory without affecting the anterograde memory functions, accompanied with a substantial rise in iNOS expression and nitric oxide levels in cerebral cortex on days 2 and 3 post hypoxia. Treatment with aminoguanidine (iNOS inhibitor ), resulted in down-regulation of the iNOS expression, attenuation of the surge of nitric oxide (NO) in cerebral cortex and reversal of retrograde memory impairment due to hypoxia. Moreover the reduced AChE activity and elevated lipid peroxidation in cerebral cortex were evident during post hypoxia re-oxygenation period, which was not observed in the hippocampus. Additionally, NO donor spermine NONOate could inhibit the AChE activity in brain homogenates in a concentration-dependent manner, which further substantiate that nitric oxide produced during post hypoxia re-oxygenation, primarily contributes to the observed inhibition of cortical AChE activity. Based on these experiments we hypothesize that the NO burst as a result of iNOS upregulation during hypoxia interrupts the memory consolidation by altering the cholinergic functions.
Subject(s)
Acetylcholinesterase/metabolism , Hypoxia/enzymology , Hypoxia/psychology , Memory Disorders/psychology , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide/metabolism , Amnesia, Anterograde/chemically induced , Amnesia, Anterograde/psychology , Amnesia, Retrograde/chemically induced , Amnesia, Retrograde/psychology , Animals , Avoidance Learning/drug effects , Blotting, Western , Cerebral Cortex/drug effects , Cerebral Cortex/enzymology , Cholinesterase Inhibitors/pharmacology , Enzyme Inhibitors/pharmacology , Glyceraldehyde-3-Phosphate Dehydrogenases/biosynthesis , Glyceraldehyde-3-Phosphate Dehydrogenases/genetics , Guanidines/pharmacology , Hippocampus/drug effects , Hippocampus/enzymology , Learning/drug effects , Lipid Peroxidation/drug effects , Male , Memory Disorders/chemically induced , Mice , Mice, Inbred BALB C , Nitric Oxide Donors/pharmacology , Nitric Oxide Synthase Type II/biosynthesis , Oxidative Stress/drug effects , RNA, Messenger/biosynthesis , RNA, Messenger/geneticsABSTRACT
The present study is aimed at evaluating the functional and neuroprotective effect of benzamide, a poly-(ADP-ribose) polymerase (PARP) inhibitor on delayed neuronal death (DND) in hippocampus CA1 region and memory impairment following global cerebral ischemia (GCI) in a mouse model. GCI was induced by bilateral common carotid artery occlusion (BCAo) for 20 min followed by reperfusion for 9 days. Postischemic continuous treatment with benzamide (160 mg/kg b w i.p. for 9 days) significantly reversed the GCI-induced anterograde memory impairment in passive avoidance step through and elevated plus maze tasks. The observed memory impairment in vehicle treated ischemia group was found to be well correlated with DND and downregulation of cholinergic muscarinic receptor-1 expression, which was possibly mediated by inflammation and apoptosis, as revealed from inducible nitric oxide synthase (iNOS) expression and number of TUNEL positive neurons in hippocampus CA1 region. It is clear from the present experiment that benzamide treatment significantly decreases the iNOS expression and number of apoptotic neurons and thereby improves the neuronal survival and memory during GCI. Our present findings provide compelling evidence that multiple doses of benzamide treatment is a promising therapeutic approach for cerebrovascular and neurodegenerative diseases, which deserves further clinical evaluation.
