Risperidone Reverses the Downregulation of BDNF in Hippocampal Neurons and MK801-Induced Cognitive Impairment in Rats

AbstractCognitive impairment in the aging population is quickly becoming a health care priority, for which currently no disease-modifying treatment is available. Multiple domains of cognition decline with age even in the absence of neurodegenerative diseases. The cellular and molecular changes leading to cognitive decline with age remain elusive. Synaptobrevin-2 (Syb2), the major vesicular SNAP receptor protein, highly expressed in the cerebral cortex and hippocampus, is essential for synaptic transmission. We have analyzed Syb2 protein levels in mice and found a decrease with age. To investigate the functional consequences of lower Syb2 expression, we have used adult Syb2 heterozygous mice (Syb2+/−) with reduced Syb2 levels. This allowed us to mimic the age-related decrease of Syb2 in the brain in order to selectively test its effects on learning and memory. Our results show that Syb2+/− animals have impaired learning and memory skills and they perform worse with age in the radial arm water maze assay. Syb2+/− hippocampal neurons have reduced synaptic plasticity with reduced release probability and impaired long-term potentiation in the CA1 region. Syb2+/− neurons also have lower vesicular release rates when compared to WT controls. These results indicate that reduced Syb2 expression with age is sufficient to cause cognitive impairment.

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Shikonin Attenuates Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment by Inhibiting Apoptosis via PTEN/Akt/CREB/BDNF Signaling

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/5564246 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Yanqiu Jia ◽

Zhe Li ◽

Tianjun Wang ◽

Mingyue Fan ◽

Jiaxi Song ◽

...

Keyword(s):

Cognitive Impairment ◽

Signaling Pathway ◽

Hippocampal Neurons ◽

Sham Group ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Terminal Deoxynucleotidyl Transferase ◽

Vehicle Group ◽

Nissl Staining ◽

Bdnf Signaling

Shikonin (SK) exerts neuroprotective effects; however, to date, its protective effect against chronic cerebral hypoperfusion- (CCH-) induced vascular dementia (VaD) has not been investigated. Therefore, the current study investigated whether SK could mitigate the cognitive deficits caused by CCH. The effects of SK treatment on the PTEN/Akt/CREB/BDNF signaling pathway and apoptosis in hippocampal neurons were examined in a rat model of VaD established via bilateral common carotid artery occlusion (BCCAO). Fifty-two rats were randomly divided into 4 groups: sham, vehicle, SK-L (10 mg/kg SK per day), and SK-H (25 mg/kg SK per day). SK was regularly administered by gavage for 2 weeks. The results of the water maze test revealed that the escape latency in the vehicle group was significantly longer than that in the sham group, and rats in the vehicle group spent a smaller proportion of time in the target quadrant than those in the sham group. SK treatment reduced the escape latencies and increased the proportion of time spent in the target quadrant. Nissl staining showed morphological damage in the CA1 areas of the hippocampus in the vehicle group. SK treatment alleviated the injuries to hippocampal neurons. Western blot analysis showed higher p-PTEN and lower p-Akt, p-CREB, and BDNF expression in the vehicle group than in the sham group. SK administration reversed the upregulation of p-PTEN and the downregulation of p-Akt, p-CREB, and BDNF. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling- (TUNEL-) positive cells in the hippocampal CA1 region of the vehicle group was significantly increased. Treatment with SK decreased the number of positive cells. Furthermore, as marker proteins of apoptosis, bcl-2 expression was decreased and bax expression was increased; thus, the ratio of bcl-2/bax was decreased in the vehicle group. SK treatment upregulated the expression of bcl-2 and downregulated the expression of bax, thereby elevating the bcl-2/bax ratio. Moreover, the aforementioned effects of SK were dose-dependent. The effect of 25 mg/kg per day was more obvious than that of 10 mg/kg per day. In conclusion, SK inhibited hippocampal neuronal apoptosis to protect against CCH-induced injury by regulating the PTEN/Akt/CREB/BDNF signaling pathway, consequently improving cognitive impairment.

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Treadmill Running Regulates Adult Neurogenesis, Spatial and Non-Spatial Learning by ErbB4 Signaling

10.21203/rs.3.rs-122649/v1 ◽

2020 ◽

Author(s):

Yandong Yi ◽

Yuanlong Song ◽

Bo Liu ◽

Yisheng Lu

Keyword(s):

Cognitive Impairment ◽

Discrimination Learning ◽

Spatial Learning ◽

Hippocampal Neurons ◽

Reference Memory ◽

Contextual Fear Conditioning ◽

Treadmill Running ◽

Spatial Learning And Memory ◽

Contextual Fear ◽

Adult Hippocampus

Abstract Recent studies have shown exercise is effective for adult hippocampus neurogenesis and memory. However, the molecular mechanism of exercise is unclear. In this study, AG1478, an ErbB4 inhibitor, was used to explore the involvement of ErbB4 receptors. Four weeks post-running, cognitive impairment was analyzed using T-maze, Morris water maze (MWM) and contextual fear discrimination learning tests, followed by histological assessment of the proliferation and survival of hippocampal neurons using Ki67, NeuN and BrdU immunostaining respectively. Expression of total and phosphate ErbB4 protein level was evaluated by Western blotting. The results showed that AG1478 significantly impaired the performances in T-maze and MWM (spatial learning and memory), contextual fear conditioning and discrimination learning paradigm (non-spatial working and reference memory), enhanced neurogenesis loss, downregulated the expression of p-ErbB4 and total ErbB4 protein, which could be reversed by running. Taken together, our study suggested that running ameliorates cognitive impairment and neurogenesis via ErbB4 signaling.

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Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner

International Journal of Molecular Sciences ◽

10.3390/ijms21093079 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3079 ◽

Cited By ~ 3

Author(s):

Abhisarika Patnaik ◽

Eleonora Spiombi ◽

Angelisa Frasca ◽

Nicoletta Landsberger ◽

Marta Zagrebelsky ◽

...

Keyword(s):

Cognitive Impairment ◽

Rett Syndrome ◽

Cortical Neurons ◽

Hippocampal Neurons ◽

Neurological Diseases ◽

Therapeutic Effects ◽

Dependent Manner ◽

Spine Density ◽

Neuronal Structure ◽

Cellular Mechanisms

The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.

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Platycodon grandiflorum Root Protects against Aβ-Induced Cognitive Dysfunction and Pathology in Female Models of Alzheimer’s Disease

Antioxidants ◽

10.3390/antiox10020207 ◽

2021 ◽

Vol 10 (2) ◽

pp. 207

Author(s):

Yunkwon Nam ◽

Soo Jung Shin ◽

Yong Ho Park ◽

Min-Jeong Kim ◽

Seong Gak Jeon ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Cognitive Dysfunction ◽

Hippocampal Neurons ◽

Hippocampal Formation ◽

Histopathological Analysis ◽

Root Extract ◽

Platycodon Grandiflorum ◽

5Xfad Mice

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by irreversible cognitive dysfunction. Amyloid beta (Aβ) peptide is an important pathological factor that triggers the progression of AD through accumulation and aggregation, which leads to AD-related pathologies that consequently affect cognitive functions. Interestingly, several studies have reported that Platycodon grandiflorum root extract (PGE), besides exhibiting other bioactive effects, displays neuroprotective, anti-neuroinflammatory, and cognitive-enhancing effects. However, to date, it is not clear whether PGE can affect AD-related cognitive dysfunction and pathogenesis. Therefore, to investigate whether PGE influences cognitive impairment in an animal model of AD, we conducted a Y-maze test using a 5XFAD mouse model. Oral administration of PGE for 3 weeks at a daily dose of 100 mg/kg significantly ameliorated cognitive impairment in 5XFAD mice. Moreover, to elucidate the neurohistological mechanisms underlying the PGE-mediated alleviative effect on cognitive dysfunction, we performed histological analysis of hippocampal formation in these mice. Histopathological analysis showed that PGE significantly alleviated AD-related pathologies such as Aβ accumulation, neurodegeneration, oxidative stress, and neuroinflammation. In addition, we observed a neuroprotective and antioxidant effect of PGE in mouse hippocampal neurons. Our findings suggest that administration of PGE might act as one of the therapeutic agents for AD by decreasing Aβ related pathology and ameliorating Aβ induced cognitive impairment.

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Hypobaric hypoxia-induced dendritic atrophy of hippocampal neurons is associated with cognitive impairment in adult rats

Neuroscience ◽

10.1016/j.neuroscience.2006.11.037 ◽

2007 ◽

Vol 145 (1) ◽

pp. 265-278 ◽

Cited By ~ 99

Author(s):

A.D.J. Titus ◽

B.S. Shankaranarayana Rao ◽

H.N. Harsha ◽

K. Ramkumar ◽

B.N. Srikumar ◽

...

Keyword(s):

Cognitive Impairment ◽

Hippocampal Neurons ◽

Hypobaric Hypoxia ◽

Adult Rats ◽

Dendritic Atrophy

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Dexmedetomidine Alleviates Hypoxia-Induced Synaptic Loss and Cognitive Impairment via Inhibition of Microglial NOX2 Activation in the Hippocampus of Neonatal Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6643171 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Xiaohui Chen ◽

Dongtai Chen ◽

Qiang Li ◽

Shuyan Wu ◽

Jiahao Pan ◽

...

Keyword(s):

Oxidative Stress ◽

Cognitive Impairment ◽

Hippocampal Neurons ◽

Neuronal Damage ◽

Neuroprotective Effect ◽

Neurological Deficits ◽

Neonatal Rats ◽

Synaptic Loss ◽

Neonatal Hypoxia ◽

Bv2 Microglia

Background. Perinatal hypoxia is a universal cause of death and neurological deficits in neonates worldwide. Activation of microglial NADPH oxidase 2 (NOX2) leads to oxidative stress and neuroinflammation, which may contribute to hypoxic damage in the developing brain. Dexmedetomidine has been reported to exert potent neuroprotection in several neurological diseases, but the mechanism remains unclear. We investigated whether dexmedetomidine acts through microglial NOX2 to reduce neonatal hypoxic brain damage. Methods. The potential role of microglial NOX2 in dexmedetomidine-mediated alleviation of hypoxic damage was evaluated in cultured BV2 microglia and neonatal rats subjected to hypoxia. In vivo, neonatal rats received dexmedetomidine (25 μg/kg, i.p.) 30 min before or immediately after hypoxia (5% O2, 2 h). Apocynin-mediated NOX inhibition and lentivirus-mediated NOX2 overexpression were applied to further assess the involvement of microglial NOX2 activation. Results. Pre- or posttreatment with dexmedetomidine alleviated hypoxia-induced cognitive impairment, restored damaged synapses, and increased postsynaptic density-95 and synaptophysin protein expression following neonatal hypoxia. Importantly, dexmedetomidine treatment suppressed hypoxia-induced microglial NOX2 activation and subsequent oxidative stress and the neuroinflammatory response, as reflected by reduced 4-hydroxynonenal and ROS accumulation, and decreased nuclear NF-κB p65 and proinflammatory cytokine levels in cultured BV2 microglia and the developing hippocampus. In addition, treating primary hippocampal neurons with conditioned medium (CM) from hypoxia-activated BV2 microglia resulted in neuronal damage, which was alleviated by CM from dexmedetomidine-treated microglia. Moreover, the neuroprotective effect of dexmedetomidine was reversed in NOX2-overexpressing BV2 microglia and diminished in apocynin-pretreated neonatal rats. Conclusion. Dexmedetomidine targets microglial NOX2 to reduce oxidative stress and neuroinflammation and subsequently protects against hippocampal synaptic loss following neonatal hypoxia.

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Transplantation of platelet-derived mitochondria alleviates cognitive impairment and mitochondrial dysfunction in db/db mice

Clinical Science ◽

10.1042/cs20200530 ◽

2020 ◽

Vol 134 (16) ◽

pp. 2161-2175

Author(s):

Hongli Ma ◽

Tao Jiang ◽

Wenxin Tang ◽

Zhi Ma ◽

Kairui Pu ◽

...

Keyword(s):

Cognitive Impairment ◽

Mitochondrial Dysfunction ◽

Hippocampal Neurons ◽

Neuronal Apoptosis ◽

Morris Water Maze Test ◽

Cognitive Behaviors ◽

Major Cardiovascular Events ◽

Potential Therapeutic Application ◽

Mitochondrial Number ◽

Minimal Invasion

Abstract Diabetes-associated cognitive impairment (DACI) can increase the risk of major cardiovascular events and death. Neuronal functionality is highly dependent on mitochondria and emerging evidence has shown that mitochondrial transplantation is a potential and effective strategy that can reduce brain injury and associated disorders. Platelets are abundant in blood and can be considered a readily available source of small-size mitochondria. These cells can be easily acquired from the peripheral blood with minimal invasion via simple venipuncture. The present study aimed to investigate whether transplantation of platelet-derived mitochondria (Mito-Plt) could improve DACI. Cognitive behaviors were assessed using the Morris water maze test in db/db mice. The results demonstrated that Mito-Plt was internalized into hippocampal neurons 24 h following intracerebroventricular injection. Importantly, one month following Mito-Plt transplantation, DACI was alleviated in db/db mice and the effect was accompanied with increased mitochondrial number, restored mitochondrial function, attenuated oxidative stress and neuronal apoptosis, as well as decreased accumulation of Aβ and Tau in the hippocampus. Taken together, the data demonstrated that transplantation of Mito-Plt attenuated cognitive impairment and mitochondrial dysfunction in db/db mice. This method may be a potential therapeutic application for the treatment of DACI.

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Roscovitine, a CDK5 Inhibitor, Alleviates Sevoflurane-Induced Cognitive Dysfunction via Regulation Tau/GSK3β and ERK/PPARγ/CREB Signaling

Cellular Physiology and Biochemistry ◽

10.1159/000485008 ◽

2017 ◽

Vol 44 (2) ◽

pp. 423-435 ◽

Cited By ~ 15

Author(s):

Jianhui Liu ◽

Junjun Yang ◽

Yinhua Xu ◽

Gang Guo ◽

Li Cai ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Dysfunction ◽

Hippocampal Neurons ◽

Glycogen Synthase ◽

Neuronal Damage ◽

Immunohistochemical Analysis ◽

Peroxisome Proliferator ◽

Neuroprotective Effects ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ

Background/Aims: Multiple exposures to anesthesia in children may increase the risk of developing cognitive impairment. Sevoflurane is an anesthetic that is commonly used in children during surgery. Cyclin-dependent kinase (CDK) 5 is involved in the regulation of sevoflurane-induced cognitive dysfunction, but the mechanistic details remain unclear. The present study evaluated the mechanism by which CDK5 mediates sevoflurane-induced cognitive dysfunction in mice. Methods: Hippocampal neurons were isolated from postnatal day 0 C57BL/6 mouse pups. Six-day-old wild-type mice were exposed to sevoflurane and then treated with the CDK5 inhibitor roscovitine. The effects on cognitive function were evaluated with the Morris water maze and neuronal damage in the hippocampus was assessed by immunohistochemical analysis. Results: CDK5 activation increased neuronal damage by inducing Tau/glycogen synthase kinase (GSK) 3β and suppressing extracellular signal-regulated kinase (ERK)/peroxisome proliferator-activated receptor (PPAR)γ/cyclic AMP response element-binding protein (CREB) signaling following exposure to sevoflurane. CDK5 inhibition by roscovitine administration alleviated sevoflurane-induced neuronal damage and cognitive impairment. Conclusions: Inhibiting CDK5 with roscovitine has neuroprotective effects against neuronal injury and cognitive dysfunction caused by sevoflurane anesthesia that are exerted via modulation of Tau/GSK3β and ERK/PPARγ/CREB signaling.

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