ABSTRACT
In the present study the role of glial activation and post synaptic toxicity in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-α indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, nitrite, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and excitotoxicity. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIα and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic neurotoxicity. Oral treatment with Memantine (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic neurotoxicity in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-α, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic neurotoxicity are the key factors in STZ induced memory impairment and neuronal cell death.
Subject(s)
Memory Disorders/chemically induced , Neuroglia/drug effects , Streptozocin/toxicity , Synapses/drug effects , Animals , Base Sequence , DNA Primers , Injections, Intraventricular , Locomotion/drug effects , Male , Neuroglia/enzymology , Neuroglia/metabolism , Neuroglia/pathology , Polymerase Chain Reaction , Rats , Rats, Sprague-Dawley , Streptozocin/administration & dosage , Synapses/pathologyABSTRACT
Homocysteine (Hcy) is a thiol-containing amino acid formed during methionine metabolism. Elevated level of Hcy is known as hyperhomocysteinemia (HHcy). HHcy is an independent risk factor for cerebrovascular diseases such as stroke, dementia, Alzheimer's disease, etc. Stroke, which is caused by interruption of blood supply to the brain, is one of the leading causes of death and disability in a number of people worldwide. The HHcy causes an increased carotid artery plaque that may lead to ischemic stroke but the mechanism is currently not well understood. Though mutations or polymorphisms in the key genes of Hcy metabolism pathway have been well elucidated in stroke, emerging evidences suggested epigenetic mechanisms equally play an important role in stroke development such as DNA methylation, chromatin remodeling, RNA editing, noncoding RNAs (ncRNAs), and microRNAs (miRNAs). However, there is no review available yet that describes the role of genetics and epigenetics during HHcy in stroke. The current review highlights the role of genetics and epigenetics in stroke during HHcy and the role of epigenetics in its therapeutics. The review also highlights possible epigenetic mechanisms, potential therapeutic molecules, putative challenges, and approaches to deal with stroke during HHcy.
Subject(s)
Epigenesis, Genetic , Homocysteine/metabolism , MicroRNAs/genetics , Stroke/genetics , Stroke/therapy , Animals , Humans , Hyperhomocysteinemia/complications , MicroRNAs/metabolism , RNA Editing/genetics , Stroke/complicationsABSTRACT
Present study was designed to investigate the status of neuroinflammation and NMDA receptor function in STZ (ICV) induced memory impaired rats. STZ produced significant increase in proinflammatory cytokines (TNF-α and IL-1ß), ROS, nitrite and mRNA and protein expression of iNOS and nNOS indicating a state of neuroinflammation in rat brain which was significantly prevented by Memantine and Ibuprofen treatment. STZ also significantly altered NMDA subunits, NR2A and NR2B protein and mRNA expression which were restored by Memantine only. The results suggest that neuroinflammatory markers might be involved in memory impairment via modulating the NMDA receptor in STZ induced memory impaired rats.
Subject(s)
Encephalitis/chemically induced , Memory Disorders/chemically induced , Receptors, N-Methyl-D-Aspartate/metabolism , Streptozocin/toxicity , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Brain/drug effects , Brain/metabolism , Cytokines/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Encephalitis/complications , Encephalitis/drug therapy , Encephalitis/metabolism , Excitatory Amino Acid Antagonists/therapeutic use , Gene Expression Regulation/drug effects , Ibuprofen/therapeutic use , Injections, Intraventricular , Male , Maze Learning/drug effects , Memantine/therapeutic use , Memory Disorders/complications , Memory Disorders/drug therapy , Motor Activity/drug effects , Nitric Oxide Synthase Type I/genetics , Nitric Oxide Synthase Type I/metabolism , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Nitrites/metabolism , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Receptors, N-Methyl-D-Aspartate/genetics , Statistics, NonparametricABSTRACT
Mitochondrial abnormalities have been identified in a large proportion of neurodegenerative diseases. Recently we have reported that intracerebroventricular (ICV) administration of okadaic acid (OKA) causes memory impairment in rat. However involvement of mitochondrial function in OKA induced memory impairment and neuronal damage has not been determined. OKA (200 ng) was administered by ICV route. After 13th day of OKA administration memory function was evaluated by Morris Water Maze test. Following completion of behavioral studies on 16th day, mitochondrial membrane potential, Ca(2+) and reactive oxygen species were evaluated in mitochondrial preparation of cortex, hippocampus, striatum and cerebellum of rat brain. While ATP, mitochondrial activity, lipid peroxidation and nitrite were investigated in synaptosomal preparation of rat brain areas. The activities and mRNA expression of apoptotic factors, caspase-3 and caspase-9, were studied in rat brain regions. The neuronal damage was also confirmed by histopathological study. OKA treated rats showed memory impairment including increased Ca(2+) and reactive oxygen species and decreased mitochondrial membrane potential, ATP and mitochondrial activity in mitochondrial preparation. There was a significant increase in lipid peroxidation and nitrite in synaptosomal preparations. Preventive treatment daily for 13 days with antidementic drugs, donepezil (5 mg/kg, p.o) and memantine (10 mg/kg, p.o), significantly attenuated OKA induced mitochondrial dysfunction, apoptotic cell death, memory impairment and histological changes. Mitochondrial dysfunction appeared as a key factor in OKA induced memory impairment and apoptotic cell death. This study indicates that clinically used antidementic drugs are effective against OKA induced adverse changes at behavioral, cellular, and histological levels and mitochondrial dysfunction.
Subject(s)
Apoptosis/drug effects , Brain/drug effects , Memory Disorders/chemically induced , Mitochondria/physiology , Okadaic Acid/toxicity , Animals , Brain/pathology , Injections, Intraventricular , Lipid Peroxidation , Male , Okadaic Acid/administration & dosage , Rats , Rats, Sprague-DawleyABSTRACT
Okadaic acid (OKA) is a potent and selective inhibitor of protein phosphatases, PP2A and PP1. In the present study, we evaluated effect of intracerebroventricular (ICV) bilateral injection of OKA (100 and 200 ng) on memory function and oxidative stress in rats. ICV injection of OKA (200 ng) produced memory impairment as evidenced by no significant decrease in latency time to reach the hidden platform in water maze test. It produced increase in malondialdehyde (MDA), nitrite level, reactive oxygen species (ROS) generation, mitochondrial calcium ion [Ca(2)](i) level and decreased glutathione (GSH) level in rat brain areas, indicating oxidative stress. Furthermore, we evaluated the effect of anti-dementia drugs memantine, a NMDA antagonist, and donepezil, a cholinesterase inhibitor, on OKA ICV induced memory impairment. Administration of memantine (10 mg/kg, p.o.) and donepezil (5 mg/kg, p.o.) for 13 days starting from the OKA injection improved performance in memory tests and also significantly restored GSH, MDA, nitrite levels, ROS generation and [Ca(2+)](i) level. This study demonstrates that the clinically used anti-dementic drugs are effective in OKA induced free radical generation and memory impairment in rats. Thus, OKA ICV induced memory impairment in rat appeared as a useful test model to screen anti-dementia drugs.
Subject(s)
Dementia/chemically induced , Dementia/drug therapy , Drug Evaluation, Preclinical/methods , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Okadaic Acid/toxicity , Animals , Brain/drug effects , Brain/metabolism , Brain/physiopathology , Calcium Signaling/drug effects , Calcium Signaling/physiology , Cholinesterase Inhibitors/pharmacology , Dementia/physiopathology , Disease Models, Animal , Donepezil , Enzyme Inhibitors/toxicity , Excitatory Amino Acid Antagonists/pharmacology , Glutathione/metabolism , Indans/pharmacology , Injections, Intraventricular , Male , Malondialdehyde/metabolism , Maze Learning/drug effects , Maze Learning/physiology , Memantine/pharmacology , Memory/drug effects , Memory/physiology , Memory Disorders/physiopathology , Neuropsychological Tests , Nitrites/metabolism , Oxidative Stress/drug effects , Oxidative Stress/physiology , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Treatment OutcomeABSTRACT
The Renin-angiotensin system, besides blood pressure regulation, affects learning and memory as evidenced by improvement of cognition in hypertensive patients being treated with AT1 receptor blockers like candesartan. The present study examined the influence of candesartan on memory impairment induced by intracerebral streptozotocin (IC STZ 0.5 mg/kg) in mice. Candesartan (0.05 mg/kg and 0.1 mg/kg, i.p.) was given for 14 days following IC STZ administration. The dose of 0.1 mg/kg significantly improved latency period in passive avoidance test. Further, treatment with 0.1 mg/kg candesartan for 14 days significantly improved spatial memory in mice in water maze test also. In another group, after memory impairment in mice following IC STZ administration, memory improving effect of a 7 days treatment with 0.1 mg/kg candesartan lasted only for 3 subsequent days in water maze task. IC STZ increased oxidative stress but pretreatment with 0.1 mg/kg candesartan decreased oxidative stress as indicated by a decrease in MDA and increase in GSH. Further, candesartan decreased free radicals as evidenced by flow cytometry. IC STZ affected cholinergic system also by increasing acetylcholine esterase activity that was restored by pretreatment with 0.1 mg/kg candesartan. Locomotor activity and serum glucose level remained unaffected by candesartan treatment. These results suggest that AT1 receptors play a facilitatory role in STZ induced memory deficit and corroborate number of human studies that AT1 receptor blockers can be used therapeutically against cognitive decline in hypertensive patients.
