Glial gap junctional communication involvement in hippocampal damage after middle cerebral artery occlusion

Xie, Mingxing; Yi, Chenju; Luo, Xiang; Xu, Shabei; Yu, Zhiyuan; Tang, Yingxin; Zhu, Wenhao; Du, Yixing; Jia, Lintao; Zhang, Qiang; Dong, Qiang; Zhang, Xia; Bu, Bitao; Wang, Wei

doi:10.1002/ana.22386

Cited by 68 publications

(83 citation statements)

References 40 publications

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“…Another explanation might be that lower remote microstructural integrity is caused by vascular damage caused by being exposed to the same vascular risk factors that caused the initial stroke event. Furthermore, based on studies in rats, stroke itself might cause spreading depression in the ipsilesional hemisphere, 11,33 which may allow the onset of secondary (Wallerian) degeneration of remote white matter after ischemic stroke. 34 However, the extent of this phenomenon should be further investigated to whether it also could explain the lower microstructural integrity in contralesional white matter as we observed in cognitively impaired patients.…”

Section: Discussionmentioning

confidence: 99%

“…6 Accumulating data suggest that, apart from temporary remote neurophysiological changes after stroke (ie, diaschisis), 7 a focal (ischemic) lesion could potentially affect longterm remote structural integrity (eg, of the hippocampus and thalamus) in the ipsilesional hemisphere after stroke, 3,[8][9][10][11] which has been associated with a worse poststroke memory performance. 11,12 Besides remote structural changes in the ipsilesional hemisphere, a few small neuroimaging studies (6-16 patients) in older patients with stroke (≥60 years) found loss of white matter integrity as remote as the contralesional hemisphere, 13 and this was associated with motor impairment ≤6 months after stroke 14,15 and poorer cognitive recovery 3 months after right middle cerebral artery stroke. 16 It is unknown whether lower microstructural integrity in areas remote from the initial stroke, including as remote as the contralesional hemisphere, is related to long-term (ie, years) cognitive dysfunction after stroke.…”

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confidence: 99%

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Remote Lower White Matter Integrity Increases the Risk of Long-Term Cognitive Impairment After Ischemic Stroke in Young Adults

Schaapsmeerders

Tuladhar

Arntz

et al. 2016

Stroke

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; however, this has never been investigated in young patients with stroke. A better understanding of Background and Purpose-Poststroke cognitive impairment occurs frequently in young patients with ischemic stroke (18 through 50 years of age). Accumulating data suggest that stroke is associated with lower white matter integrity remote from the stroke impact area, which might explain why some patients have good long-term cognitive outcome and others do not. Given the life expectancy of decades in young patients, we therefore investigated remote white matter in relation to long-term cognitive function. Methods-We included all consecutive first-ever ischemic stroke patients, left/right hemisphere, without recurrent stroke or transient ischemic attack during follow-up, aged 18 through 50 years, admitted to our university medical center between 1980 and 2010. One hundred seventeen patients underwent magnetic resonance imaging scanning including a T1-weighted scan, a diffusion tensor imaging scan, and completed a neuropsychological assessment. Patients were compared with a matched stroke-free control group (age, sex, and education matched). Cognitive impairment was defined as >1.5 SD below the mean cognitive index score of controls and no cognitive impairment as ≤1 SD. Tract-Based Spatial Statistics was used to assess the white matter integrity (fractional anisotropy and mean diffusivity). Results-About 11 years after ischemic stroke, lower remote white matter integrity was associated with a worse long-term cognitive performance. A lower remote white matter integrity, even in the contralesional hemisphere, was observed in cognitively impaired patients (n=25) compared with cognitively unimpaired patients (n=71). Conclusions-These findings indicate that although stroke has an acute onset, it might have long lasting effects on remote white matter integrity and thereby increases the risk of long-term cognitive impairment. (Stroke. 2016;47:2517-2525.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Remote Lower White Matter Integrity Increases the Risk of Long-Term Cognitive Impairment After Ischemic Stroke in Young Adults

Schaapsmeerders

Tuladhar

Arntz

et al. 2016

Stroke

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“…Expression of Bcl-2-positive neurons at various time points in the cortex and the hippocampus following ischemia̸reperfusion (mean ± standard deviation). (11) demonstrated that the hippocampal CA1 area ipsilateral to the occluded MCA may undergo delayed neuronal death and the process may be due to the spread of injury signals through the astrocytic gap junction from the infarct region to the remote hippocampus. Neurological impairment mediated by neuron apoptosis was confirmed by the experiment.…”

Section: Cortexmentioning

confidence: 99%

Effects of apoptosis-related proteins caspase-3, Bax and Bcl-2 on cerebral ischemia rats

et al. 2013

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Abstract. Neuron apoptosis is known to mediate a change of ethology following cerebral ischemia̸reperfusion injury in rats. Additionally, Bcl-2, Bax and caspase-3 proteins may exert a significant effect on neuron injury. The aim of this study was to investigate the role, mechanism of action and clinical significance of these proteins in neuron apoptosis and functional impairment following cerebral ischemia̸reperfusion injury in rats. Sixty male healthy adult Wistar rats were randomly assigned into control (n=6), sham operation (n=6) and experimental (n=48) groups. The model of rat cerebral ischemia̸reperfusion injury was set up according to the method of Zea-Longa. Eight subsets of 6 rats̸subset were designed according to time points (at 3, 6, 12, 24 and 48 h and at 3, 7 and 14 days). Nerve functional injury was evaluated and graded using nerve function score, balance, coordination function detection and measurement of forelimb placing. The neurons expressing caspase-3, Bax and Bcl-2 in the cortical area, CA3, CA1, stratum lucidum (Slu) and molecular layer of the dentate gyrus (MoDG) of the hippocampus were detected using immunohistochemistry or the TUNEL method. The expression of caspase-3, Bax and Bcl-2 genes was detected by the reverse transcriptase polymerase chain reaction (RT-PCR). The results indicated that, compared to the sham operation group, the score of nerve function and balance beam walking were distinctly higher (P<0.01) and the percentage of rat foreleg touching the angle or margin of the table was significantly lower in the experimental rat group (P<0.01) at 3 h following reperfusion. The expression of TUNEL-positive neurons was high in the cortical area and the CA3 region of the hippocampus (P<0.01), caspase-3 was at peak value in the cortical area and the CA1 region of the hippocampus (P<0.01), Bax was increased in the cortical area and the Slu of the hippocampus (P<0.01) and Bcl-2 was low in the cortical area and the MoDG of the hippocampus (P<0.01) in the experimental group at 48 h following reperfusion. In conclusion, cerebral ischemia/ reperfusion injury may cause neurological impairment and lead to a change of ethology, and neuron apoptosis may be associated with the activation of caspase-3 and Bax and the downregulation of Bcl-2.

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“…Another study suggested that blocking gap-junctional communication with CBX or downregulating Cx43 increases the survival of pyramidal neurons in the ipsilateral hippocampus and improves behavioral scores in the rodent model of middle cerebral artery occlusion (MCAO) [27] .…”

Section: Introductionmentioning

confidence: 99%

Protective effects of carbenoxolone are associated with attenuation of oxidative stress in ischemic brain injury

Zhang

Jing

et al. 2013

Neurosci. Bull.

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Accumulating evidence has suggested that the gap junction plays an important role in the determination of cerebral ischemia, but the underlying mechanisms remain to be elucidated. In this study, we assessed the effect of a gap-junction blocker, carbenoxolone (CBX), on ischemia/reperfusion-induced brain injury and the possible mechanisms. By using the transient cerebral ischemia model induced by occlusion of the middle cerebral artery for 30 min followed by reperfusion for 24 h, we found that pre-administration of CBX (25 mg/kg, intracerebroventricular injection, 30 min before cerebral ischemic surgery) diminished the infarction size in rats. And this was associated with a decrease of reactive oxygen species generation and inhibition of the activation of astrocytes and microglia. In PC12 cells, H 2 O 2 treatment induced more coupling and apoptosis, while CBX partly inhibited the opening of gap junctions and improved the cell viability. These results suggest that cerebral ischemia enhances the opening of gap junctions. Blocking the gap junction with CBX may attenuate the brain injury after cerebral ischemia/reperfusion by partially contributing to amelioration of the oxidative stress and apoptosis.

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Glial gap junctional communication involvement in hippocampal damage after middle cerebral artery occlusion

Abstract: Astroglial GJC plays a significant role in MCAO-induced remote hippocampal damage and cognitive impairment. It might be possible to improve the cognition in patients with MCAO by manipulating interastrocytic communication via the gap junction channels.

Cited by 68 publications

References 40 publications

Remote Lower White Matter Integrity Increases the Risk of Long-Term Cognitive Impairment After Ischemic Stroke in Young Adults

Remote Lower White Matter Integrity Increases the Risk of Long-Term Cognitive Impairment After Ischemic Stroke in Young Adults

Effects of apoptosis-related proteins caspase-3, Bax and Bcl-2 on cerebral ischemia rats

Protective effects of carbenoxolone are associated with attenuation of oxidative stress in ischemic brain injury

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