Activation of GABAB2 subunits alleviates chronic cerebral hypoperfusion-induced anxiety-like behaviours: A role for BDNF signalling and Kir3 channels

Lu, Yun; Li, Changjun; Chen, Cheng; Luo, Pan; Cai, Li; Xu, Xulin; Lü, Qing; He, Zhi; Guo, Lan

doi:10.1016/j.neuropharm.2016.08.007

Cited by 18 publications

(13 citation statements)

References 64 publications

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“…Furthermore, the activation of the ACE/Ang II/AT1R axis also causes no hypertensive disorders, such as cerebral hypoperfusion and ischemic injury [44][45][46]. Those disorders induced anxiety-like behavior and memory loss [14,47]. In our study, relative to SHR, CCH in SHR induced significantly activation of the ACE/Ang II/AT1R axis and exacerbated anxiety-like behavior and memory deficits.…”

Section: Discussionsupporting

confidence: 50%

“…In addition, accumulating evidence suggests that cerebral hypoperfusion and hypertension have an interdependent relationship and promote the development of memory impairment [10][11][12][13]. CCH [14,15] and hypertension [16] are risk factors for anxiety, but the effect of their comorbidity on anxiety is unclear. Therefore, the role of CCH with hypertension in the development of anxiety and memory impairment requires elucidation.…”

Section: Introductionmentioning

confidence: 99%

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Electroacupuncture Improved Chronic Cerebral Hypoperfusion-Induced Anxiety-Like Behavior and Memory Impairments in Spontaneously Hypertensive Rats by Downregulating the ACE/Ang II/AT1R Axis and Upregulating the ACE2/Ang-(1-7)/MasR Axis

Feng

Líu

et al. 2020

Neural Plasticity

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Electroacupuncture (EA) can effectively alleviate anxiety disorders and memory impairments caused by various neurodegenerative diseases; however, the molecular mechanisms underlying its neuroprotective effects are unclear. Previous studies have shown that the renin-angiotensin system (RAS) comprises of two axes with mutual antagonism: the classical angiotensin converting enzyme/angiotensin II/angiotensin II type 1 receptor (ACE/Ang II/AT1R) axis and the protective angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor (ACE2/Ang-(1-7)/MasR) axis. In this study, we observed that chronic cerebral hypoperfusion (CCH) mediated anxiety-like behavior and memory impairments in spontaneously hypertensive rats (SHR) via upregulation of the hippocampal classical axis (ACE/Ang II/AT1R) and the partial hippocampal protective axis (ACE2/Ang-(1-7)). However, Ang II levels were much higher than those of Ang-(1–7), indicating that the ACE/Ang II/AT1R axis plays a dominant role in the comorbidity of CCH and hypertension. Moreover, candesartan cilexetil (Canc) and perindopril (Peril) were used as positive control drugs. We found that EA, Canc, and Peril attenuated CCH-induced anxiety-like behavior and memory impairments in SHR, potentially via downregulation of the hippocampal classical axis (ACE/Ang II/AT1R) and upregulation of the whole hippocampal protective axis (ACE2/Ang-(1-7)/MasR). These results suggest that EA therapy for CCH with hypertension may be mediated by two hippocampal RAS axes.

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Section: Discussionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Electroacupuncture Improved Chronic Cerebral Hypoperfusion-Induced Anxiety-Like Behavior and Memory Impairments in Spontaneously Hypertensive Rats by Downregulating the ACE/Ang II/AT1R Axis and Upregulating the ACE2/Ang-(1-7)/MasR Axis

Feng

Líu

et al. 2020

Neural Plasticity

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“…The mechanism was that baclofen attenuated the decrease of surface expression of GABAB R1 and GABAB R2 and restored the balanced surface expression of HCN1/HCN2, which coregulated neuronal excitability with GABA receptors in the rat hippocampal CA1 area [ 4 ]. In another research, baclofen ameliorated cognitive deficits 2VO in rats by improving BDNF signaling and reverse Kir3 channel surface expressions in the hippocampal CA1 [ 60 ]. It has been proved that activation of GABA(B) receptors triggers the secretion of BDNF and promotes the maturation of GABAergic synapses in the newborn mouse hippocampus [ 61 ].…”

Section: Improvement Of Cognitive Function By Regulating Gabaergicmentioning

confidence: 99%

The Effects of GABAergic System under Cerebral Ischemia: Spotlight on Cognitive Function

Chen

Guo

et al. 2020

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In this review, we present evidence about the changes of the GABAergic system on the hippocampus under the ischemic environment, which may be an underlying mechanism to the ischemia-induced cognitive deficit. GABAergic system, in contrast to the glutamatergic system, is considered to play an inhibitory effect on the central nervous system over the past several decades. It has received widespread attention in the area of schizophrenia and epilepsy. The GABAergic system has a significant effect in promoting neural development and formation of local neural circuits of the brain, which is the structural basis of cognitive function. There have been a number of reviews describing changes in the GABAergic system in cerebral ischemia in recent years. However, no study has investigated the changes in the system in the hippocampus during cerebral ischemic injury, which results in cognitive impairment, particularly at the chronic ischemic stage and the late phase of ischemia. We present a review of the changes of the GABAergic system in the hippocampus under ischemia, including GABA interneurons, extracellular GABA neurotransmitter, and GABA receptors. Several studies are also listed correlating amelioration of cognitive impairment by regulating the GABAergic system in the hippocampus damaged under ischemia. Furthermore, exogenous cell transplantation, which improves cognition by modulating the GABAergic system, will also be described in this review to bring new insight and strategy on solving cognitive deficits caused by cerebral ischemia.

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“…Stereotaxic injection was performed as we described previously [36] under anesthesia with pentobarbital sodium (40 mg/kg, intraperitoneal injection, i.p.). Three weeks after shRNA infusion, we randomly selected half of the HCN2-shRNA-infected rats to determine the injection site and infection efficiency, and then carried out further studies as described below.…”

Section: Lentiviral Transductionmentioning

confidence: 99%

“…Three days after TGCI injury, we began Morris water maze training as described previously [30,36], and recorded swim speed, latency to escape onto the hidden platform, proportion of time spent in the target quadrant, and amount of time spent in the quadrant of the former platform position with a video camera linked to a computer-based image analyzer (Morris water-maze tracking system MT-200; Chengdu Technology and Market Co., Ltd, Chengdu, China).…”

Section: Water Maze Taskmentioning

confidence: 99%

Blockade of HCN2 Channels Provides Neuroprotection Against Ischemic Injury via Accelerating Autophagic Degradation in Hippocampal Neurons

et al. 2020

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In the central nervous system, hyperpolarizationactivated cyclic nucleotide-gated (HCN) channels are essential to maintain normal neuronal function. Recent studies have shown that HCN channels may be involved in the pathological process of ischemic brain injury, but the mechanisms remain unclear. Autophagy is activated in cerebral ischemia, but its role in cell death/survival remains controversial. In this study, our results showed that the HCN channel blocker ZD7288 remarkably decreased the percentage of apoptotic neurons and corrected the excessive autophagy induced by oxygen-glucose deprivation followed by reperfusion (OGD/R) in hippocampal HT22 neurons. Furthermore, in the OGD/R group, p-mTOR, p-ULK1 (Ser 757), and p62 were significantly decreased, while p-ULK1 (Ser 317), atg5, and beclin1 were remarkably increased. ZD7288 did not change the expression of p-ULK1 (Ser 757), ULK1 (Ser 317), p62, Beclin1, and atg5, which are involved in regulating autophagosome formation. Besides, we found that OGD/R induced a significant increase in Cathepsin D expression, but not LAMP-1. Treatment with ZD7288 at 10 lmol/L in the OGD/R group did not change the expression of cathepsin D and LAMP-1. However, chloroquine (CQ), which decreases autophagosome-lysosome fusion, eliminated the correction of excessive autophagy and neuroprotection by ZD7288. Besides, shRNA knockdown of HCN2 channels significantly reduced the accumulation of LC3-II and increased neuron survival in the OGD/R and transient global cerebral ischemia (TGCI) models, and CQ also eliminated the effects of HCN2-shRNA. Furthermore, we found that the percentage of LC3-positive puncta that co-localized with LAMP-1-positive lysosomes decreased in Con-shRNAtransfected HT22 neurons exposed to OGD/R or CQ. In HCN2-shRNA-transfected HT22 neurons, the percentage of LC3-positive puncta that co-localized with LAMP-1-positive lysosomes increased under OGD/R; however, the percentage was significantly decreased by the addition of CQ to HCN2-shRNA-transfected HT22 neurons. The present results demonstrated that blockade of HCN2 channels provides neuroprotection against OGD/R and TGCI by accelerating autophagic degradation attributable to the promotion of autophagosome and lysosome fusion.

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Activation of GABAB2 subunits alleviates chronic cerebral hypoperfusion-induced anxiety-like behaviours: A role for BDNF signalling and Kir3 channels

Cited by 18 publications

References 64 publications

Electroacupuncture Improved Chronic Cerebral Hypoperfusion-Induced Anxiety-Like Behavior and Memory Impairments in Spontaneously Hypertensive Rats by Downregulating the ACE/Ang II/AT1R Axis and Upregulating the ACE2/Ang-(1-7)/MasR Axis

Electroacupuncture Improved Chronic Cerebral Hypoperfusion-Induced Anxiety-Like Behavior and Memory Impairments in Spontaneously Hypertensive Rats by Downregulating the ACE/Ang II/AT1R Axis and Upregulating the ACE2/Ang-(1-7)/MasR Axis

The Effects of GABAergic System under Cerebral Ischemia: Spotlight on Cognitive Function

Blockade of HCN2 Channels Provides Neuroprotection Against Ischemic Injury via Accelerating Autophagic Degradation in Hippocampal Neurons

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