DNA hypomethylation promotes learning and memory recovery in a rat model of cerebral ischemia/reperfusion injury

Cerebral ischemia/reperfusion injury impairs learning and memory in patients.Studies have shown that synaptic function is involved in the formation and development of memory,and that DNA methylation plays a key role in the regulation of learning and memory.To investigate the role of DNA hypomethylation in cerebral ischemia/reperfusion injury,in this study,we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery and then treated the rats with intraperitoneal 5-aza-2′-deoxycytidine,an inhibitor of DNA methylation.Our results showed that 5-aza-2′-deoxycytidine markedly improved the neurological function,and cognitive,social and spatial memory abilities,and dose-dependently increased the synaptic density and the expression of SYP and SHANK2 proteins in the hippocampus in a dose-dependent manner in rats with cerebral ischemia/reperfusion injury.The effects of 5-aza-2′-deoxycytidine were closely related to its reduction of genomic DNA methylation and DNA methylation at specific sites of the Syp and Shank2 genes in rats with cerebral ischemia/reperfusion injury.These findings suggest that inhibition of DNA methylation by 5-aza-2′-deoxycytidine promotes the recovery of learning and memory impairment in a rat model of cerebral ischemia/reperfusion injury.These results provide theoretical evidence for stroke treatment using epigenetic methods.

Relationship of cerebral arterial stenosis to cognitive and memory disorders

BACKGROUND: Cerebral arterial stenosis can cause cerebral hypoperfusion, and than result in the decline of cognitive function, whereas the cognitive dysfunction induced by different cerebral arterial stenosis have different manifestations and types. OBJECTIVE: To observe the differences of cognitive and memory dysfunctions in patients with cerebral arterial stenosis of different types. DESIGN: A comparative observation. SETTING: Affiliated Hospital of Jining Medical College. PARTICIPANTS: Forty-two outpatients or inpatients with cerebral arterial stenosis were selected from the Department of Neurology, Affiliated Hospital of Jining Medical College from February 2005 to January 2006, including 25 males and 17 females. There were 18 cases of internal carotid arterial stenosis, 14 cases of vertebrobasilar arterial stenosis and 10 cases of whole cerebral arterial stenosis. The diagnostic standards for cerebral arterial stenosis were identified according to North American Symptomatic Carotid Endarterectomy Trial (NASCET). Meanwhile, 18 healthy physical examinees were enrolled as the control group, including 10 males and 8 females, aged 58-80 years old. All the enrolled subjects were informed and agreed with the detection and evaluation. METHODS: ① The memory function was evaluated using revised Wechsler memory scale for adults, including long-term memory (experience, orientation and counting), short-term memory (visual recognition, picture memory, visual regeneration, association and thigmesthesia) and sensory memory (forward and backward recitation of numbers). The scale scores were turned to memory quotients. The higher the scores, the better the memory function. ② The cognitive function was evaluated using revised Wechsler adult intelligence scale: It consisted of eleven subtests, including six language scales (information, digit span, vocabulary, arithmetics, apprehension, similarity) and five operation scales (picture completion, picture arrangement, block design, geometric design, digit-symbol test). The intelligence quotients were obtained. The higher the scores, the better the cognitive function. MAIN OUTCOME MEASURES: Results of memory and cognitive function test in patients with cerebral arterial stenosis of different types. RESULTS: All the 42 patients with cerebral artery stenosis and 11 healthy subjects were involved in the final analysis of results. ① Results of memory function test: The memory function was worse in the arterial stensis groups than in the control group (P < 0.05-0.01). There were very significant differences in the scores of orientation, association and picture memory between the internal carotid arterial stenosis group and control group (P < 0.01). There were also very significant differences in the scores of counting, logic memory, forward and backward recitation of numbers, visual regeneration, visual recognition and thigmesthesia between the vertebrobasilar arterial stenosis group and control group (P < 0.01). Except experience and visual regeneration, there were significant very differences in the scores of the other tests between the whole cerebral arterial stenosis group and control group (P < 0.01). The memory quotient was obviously lower in the vertebrobasilar arterial stenosis group than in the internal carotid arterial stenosis group [(72.31±26.46), (87.38±21.86) points, P < 0.05], and it was the lowest in the whole cerebral arterial stenosis group [(63.74±25.25) points]. ② Results of cognitive function test: The cognitive function was worse in the arterial stensis groups than in the control group (P < 0.05-0.01). There were very significant differences in the scores of apprehension, arithmetics, similarity, digit-symbol test, picture completion and block design between the internal carotid arterial stenosis group and control group (P < 0.01). There were also very significant differences in the scores of backward recitation of numbers, vocabulary and geometric design between the vertebrobasilar arterial stenosis group and control group (P < 0.01). Except information, there were significant very differences in the scores of the other tests between the whole cerebral arterial stenosis group and control group (P < 0.01). The intelligence quotient was obviously lower in the internal carotid arterial stenosis group than in the vertebrobasilar arterial stenosis group [(72.65±23.39), (81.34±25.46) points, P < 0.05], and it was the lowest in the whole cerebral arterial stenosis group [(65.98±27.34) points]. CONCLUSION: Different cerebral arterial stenosis can induce different cognitive dysfunctions. The main manifestation of the patients with internal carotid arterial stenosis was the declined cognitive function, and that in patients with vertebrobasilar arterial stenosis was the declined memory, and the decrease of total intelligence was more obvious in the formers than in the latters, whereas the decrease of total memory quotient was more obvious in the patients with vertebrobasilar arterial stenosis; The cognitive and memory dysfunction were the most serious in patients with whole cerebral arterial stenosis.

Neuroprotective Effects of Electroacupuncture Preventive Treatment in Senescence-Accelerated Mouse Prone 8 Mice

Objective： To investigate the preventive treatment effects of electroacupuncture（EA） on cognitive changes and brain damage in senescence-accelerated mouse prone 8（SAMP8） mice. Methods： The 5-month-old male SAMP8 and age-matched homologous normal aging mice（SAMR1） were adopted in this study. EA stimulation at Baihui（GV 20） and Yintang（EX-HN 3） was performed every other day for 12 weeks, 4 weeks as a course. Morris water maze test and Nissl-stained with cresyl violet were used for cognitive impairments evaluation and brain morphometric analysis. Amyloid-β（Aβ） expression in hippocampus and parietal cortex was detected by immunohistochemistry, and apoptosis was observed by TUNEL staining. Results： After 3 courses of EA preventive treatment, the escape latencies of 8-month-old SAMP8 mice in EA group were significantly shortened than those of un-pretreated SAMP8 mice. Compared with SAMR1 mice, extensive neuronal changes were visualized in the CA1 area of hippocampus in SAMP8 mice, while these pathological changes and attenuate cell loss in hippocampal CA1 area of SAMP8 mice markedly reduced after EA preventive treatment. Furthermore, Aβ expression in hippocampus and parietal cortex of SAMP8 mice decreased significantly after EA treatment, and neuronal apoptosis decreased as well. Conclusion： EA preventive treatment at GV 20 and EX-HN 3 might improve cognitive deficits and neuropathological changes in SAMP8 mice, which might be, at least in part, due to the effects of reducing brain neuronal damage, decreasing neuronal apoptosis and inhibiting Aβ-containing aggregates.

Can multi-modal neuroimaging evidence from hippocampus provide biomarkers for the progression of amnestic mild cognitive impairment?

Impaired structure and function of the hippocampus is a valuable predictor of progression from amnestic mild cognitive impairment（a MCI） to Alzheimer＇s disease（AD）. As a part of the medial temporal lobe memory system,the hippocampus is one of the brain regions affected earliest by AD neuropathology,and shows progressive degeneration as a MCI progresses to AD. Currently,no validated biomarkers can precisely predict the conversion from a MCI to AD. Therefore,there is a great need of sensitive tools for the early detection of AD progression. In this review,we summarize the specifi c structural and functional changes in the hippocampus from recent a MCI studies using neurophysiological and neuroimaging data. We suggest that a combination of advanced multi-modal neuroimaging measures in discovering biomarkers will provide more precise and sensitive measures of hippocampal changes than using only one of them. These will potentially affect early diagnosis and disease-modifying treatments. We propose a new sequential and progressive framework in which the impairment spreads from the integrity of fibers to volume and then to function in hippocampal subregions. Meanwhile,this is likely to be accompanied by progressive impairment of behavioral and neuropsychological performance in the progression of a MCI to AD.