Research reportTime course of motor and cognitive functions after chronic cerebral ischemia in rats
Introduction
Cerebral ischemia is defined as condition characterized by insufficient blood flow to the brain, which will alter normal cellular function. Moreover, cerebral ischemia is one of the leading causes of death and long-term disability in aging populations, due to the frequency occurrence of irreversible brain damage and subsequent loss of neuronal function [12]. Chronic cerebral ischemia (CCI) can induce the accumulation of nitric oxide (NO) and reactive oxygen species (ROS), leading to neurons injury in selective, vulnerable regions of the brain, especially the hippocampus and cerebral cortex, and subsequent cognitive impairments and motor dysfunction [11], [18], [25]. Furthermore, chronic cerebral ischemia has been considered as the major cause of vascular dementia and Alzheimer's disease (AD), characterized by neurodegeneration and cognitive impairment with advancing age [27].
Several animal models have been developed to create ischemic injuries with various degrees of severity in the rat brain, allowing detailed examinations of the cellular and metabolic mechanisms and behavioral consequences of disrupted cerebral circulation. Techniques such as ligation of specific, large arteries that supply the brain create conditions of cerebral hypoperfusion and trigger the pathophysiological changes in the brain, leading to neuronal damage of the brain [1], [8]. Further, some occlusion models, such as the two-vessel occlusion of the common carotid arteries, give rise to ischemic cell changes in brain areas including the hippocampal CA1 subfield, striatum, and neocortex. Interestingly, the damage induced by two-vessel occlusion of the common carotid arteries appears to be similar in size and location as the injury typically seen with four-vessel occlusion models [13].
It is noteworthy that, in addition to mimicking acute ischemic insults, some occlusion models also capture conditions of more chronic hypoperfusion of the cerebrum. According to Tsuchiya et al. [21], permanent bilateral occlusion of the common carotid arteries is a model of chronic cerebral hypoperfusion, which could lead to cognitive impairments such as those seen in Alzheimer's disease and vascular dementia. The progressive neuronal degeneration and cholinergic dysfunction following permanent bilateral occlusion of the common carotid arteries can result in long-lasting cognition deficits in rat [14]. Furthermore, Scherr at al. [17] suggested that chronic blood flow restrictions may cause or exacerbate the cognitive decline seen in various forms of human dementia, a notion that emphasizes the importance of developing and evaluating novel animal models of chronic hypoperfusion. In fact, a thorough evaluation of the functional outcomes over the course of several weeks after ischemia is a key component in improving the clinical relevance of experimental dementia studies.
Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family, potently promote cell proliferation, cell differentiation, and neuronal protection and regulate the synaptic function in the central nervous system by stimulating intracellular signaling pathway [15]. BDNF also play important role in neurogenesis, long-term potentiation (LTP), learning and memory, and mood changes [24]. Moreover, clinical studies have suggested that low level of BDNF cause reduction in hippocampal volume which leads to age related spatial memory impairments [6].
The present study was conducted to provide a real time course of the neurobehavioral outcome following the chronic cerebral ischemia induced by PBOCCA in rats. A battery of behavioral tests were administered over the course of a 4-week period following the PBOCCA procedure, with tests chosen to assess both cognitive and motoric functions, thus providing a detailed behavioral and temporal profile of the neurobehavioral functions that are impaired and spared as a result of chronic brain ischemia. The effect of chronic cerebral ischemia on BDNF expression and morphological changes in hippocampal CA1 region also were examined in this study.
Section snippets
Animals
Male Sprague Dawley (SD) rats weighing 200–300 g were obtained from the breeding colony of the Animal Research and Service Centre (ARASC), Universiti Sains Malaysia (USM). They were housed five rats per cage and maintained at a constant temperature on a standard 12:12 light/dark cycle with light on at 7 am. Food and water were given ad libitum. The experiments were conducted according to the approval of the Animal Ethics Committee Universiti Sains Malaysia with the reference number USM/Animal
Locomotor activity
The locomotor activity during 20 min open field test sessions for both the PBOCCA and sham-operated group is presented in Fig. 1. Unpaired Student's t-test did not reveal a significant difference in locomotor activity between the groups at1 week (p = 0.3035), 2 weeks (p = 0.6106), 3 weeks (p = 0.5339), and 4 weeks (p = 0.3961) after the surgery, indicating that PBOCCA did not impair motor performance.
Passive avoidance task
Memory functions of PBOCCA rats and sham-operated animals were assessed by a passive avoidance task.
Discussion
The permanent bilateral occlusion of the common carotid arteries using the two-vessel occlusion method (PBOCCA) in rats is known to cause significant reductions of cerebral blood flow, thus providing a useful animal model of chronic brain ischemia to examine hypoperfusion-induced neuronal damage and cognitive impairments, as well as some aspects of non-pathological human aging and Alzheimer's Disease [7], [20]. A review paper on chronic ischemia by Farkas et al. [8] stated that the cognitive
Conclusion
This study provides further evidence that chronic cerebral ischemia due to PBOCCA in rats results in severe and long-lasting cognitive impairments in several learning and memory (passive avoidance, spatial navigation), without affecting spontaneous locomotor activity measured in an open field apparatus. Furthermore, the decrease in BDNF expression in hippocampus after PBOCCA may aggravate the cognitive impairment. Our observation also confirm the notion that the PBOCCA rat model may capture
Acknowledgements
Financial support was received from Ministry of Higher Education (MOHE) Malaysia and Universiti Sains Malaysia special funding for the project of Fundamental Neuroscience-Neurobehaviour (304/CNEURO/652201/K134).
References (27)
- et al.
BDNF and memory processing
Neuropharmacology
(2014) - et al.
Chronic brain hypoperfusion causes early glial activation and neuronal death, and subsequent long-term memory impairment
Brain Res. Bull.
(2012) - et al.
Chronic cerebral hypoperfusion: loss of pupillary reflex, visual impairment and retinal neurodegeneration
Brain Res
(2000) - et al.
Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases
Brain Res Rev
(2007) - et al.
Free radical spin trap α-phenyl-N-tert-butyl-nitron inhibits caspase-3 activation and reduces brain damage following a severe forebrain ischemic injury
Free Radic Biol Med
(2001) - et al.
Rodent models of global cerebral ischemia: a comparison of two-vessel occlusion and four-vessel occlusion
Gen Pharmacol
(1998) - et al.
Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat
Brain Res
(1995) - et al.
Chronic reduction of cerebral blood flow in the adult rat: late-emerging CA1 cell loss and memory dysfunction
Brain Res
(1996) - et al.
Neuronal damage, central cholinergic dysfunction and oxidative damage correlate with cognitive deficits in rats with chronic cerebral hypoperfusion
Neurobiol Learn Mem
(2014) - et al.
Protective effect of Oren-gedoku-to (Huang-Lian-Jie-Du-Tang) against impairment of learning and memory induced by transient cerebral ischemia in mice
J Enthnopharmacol
(2000)
Role of brain-derived neurotrophic factor in learning and memory
Life Sci
Neurovascular mechanisms of Alzheimer's neurodegeneration
Trends Neurosci
Animal models of ischemic stroke. Part two: Modeling cerebral ischemia
Open Neurol J
Cited by (40)
The nootropic and anticholinesterase activities of Clitoria ternatea Linn. root extract: Potential treatment for cognitive decline
2020, Neurochemistry InternationalTRPM4 inhibition improves spatial memory impairment and hippocampal long-term potentiation deficit in chronic cerebral hypoperfused rats
2020, Behavioural Brain ResearchCitation Excerpt :Providing the molecular and cellular substrates of synaptic mechanisms underlying learning and memory formation, LTP in the hippocampus is considered as the primary experimental model for investigating the synaptic basis of learning and memory [28]. Large body of experimental evidence suggests that CCH impaired the LTP in the hippocampal CA1 region of the rats [5,6,15,18]. As in the hippocampus, CA1 region is the most vulnerable to cerebral hypoperfusion.