title: Transient focal cerebral ischemia induces long-term cognitive function deficit in an experimental ischemic stroke model.
abstract: Vascular dementia ranks as the second leading cause of dementia in the United States. However, its underlying pathophysiological mechanism is not fully understood and no effective treatment is available. The purpose of the current study was to evaluate long-term cognitive deficits induced by transient middle cerebral artery occlusion (tMCAO) in rats and to investigate the underlying mechanism. Sprague-Dawley rats were subjected to tMCAO or sham surgery. Behavior tests for locomotor activity and cognitive function were conducted at 7 or 30days after stroke. Hippocampal long term potentiation (LTP) and involvement of GABAergic neurotransmission were evaluated at 30days after sham surgery or stroke. Immunohistochemistry and Western blot analyses were conducted to determine the effect of tMCAO on cell signaling in the hippocampus. Transient MCAO induced a progressive deficiency in spatial performance. At 30days after stroke, no neuron loss or synaptic marker change in the hippocampus were observed. LTP in both hippocampi was reduced at 30days after stroke. This LTP impairment was prevented by blocking GABAA receptors. In addition, ERK activity was significantly reduced in both hippocampi. In summary, we identified a progressive decline in spatial learning and memory after ischemic stroke that correlates with suppression of hippocampal LTP, elevation of GABAergic neurotransmission, and inhibition of ERK activation. Our results indicate that the attenuation of GABAergic activity or enhancement of ERK/MAPK activation in the hippocampus might be potential therapeutic approaches to prevent or attenuate cognitive impairment after ischemic stroke.
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.forename: Renqi
authors.initials: R
authors.lastname: Huang
authors.forename: Ritu A
authors.initials: RA
authors.lastname: Shetty
authors.forename: Nopporn
authors.initials: N
authors.lastname: Thangthaeng
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.forename: Zhenglan
authors.initials: Z
authors.lastname: Chen
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sumien
authors.forename: Margaret
authors.initials: M
authors.lastname: Rutledge
authors.forename: Glenn H
authors.initials: GH
authors.lastname: Dillon
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Forster
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Yang
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003072:Cognition Disorders / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000502:physiology*; D006624:Hippocampus / Q000503:physiopathology; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014796:Visual Perception / Q000502:physiology
chemical_list: D000697:Central Nervous System Stimulants; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010852:Picrotoxin
keywords: Cognition; ERK; GABA; Hippocampus; Long term potentiation; Stroke; Vascular dementia