Mitochondrial Proteins Unveil the Mechanism by Which Physical Exercise Ameliorates Memory, Learning and Motor Activity in Hypoxic Ischemic Encephalopathy Rat Model

Gendi, Fred; Pei, Feifei; Wang, Yuan; Li, Haoye; Fu, Jia; Chang, Cheng

doi:10.3390/ijms23084235

Cited by 6 publications

(5 citation statements)

References 33 publications

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“…The GO analysis indicated that the downregulated DEGs were mainly associated with biological processes related to nervous system development, neuron generation, and neurogenesis. Increasing evidence has demonstrated that the disruption of neurogenesis in the hippocampus significantly contributes to the development of cognitive impairment following neonatal HIBD 35,36 . The activation of the BDNF/TrkB signaling pathway plays a crucial role in reducing cell death in the vicinity of lesions, repairing neuronal damage, and facilitating neurogenesis 37 .…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence has demonstrated that the disruption of neurogenesis in the hippocampus significantly contributes to the development of cognitive impairment following neonatal HIBD. 35 , 36 The activation of the BDNF/TrkB signaling pathway plays a crucial role in reducing cell death in the vicinity of lesions, repairing neuronal damage, and facilitating neurogenesis. 37 To identify a potential therapeutic target for treating neonatal HIBD, we investigated the neuroprotective effects of DEX on neurogenesis in the hippocampus through the BDNF/TrkB pathway.…”

Section: Discussionmentioning

confidence: 99%

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Dexmedetomidine alleviates cognitive impairment by promoting hippocampal neurogenesis via BDNF/TrkB/CREB signaling pathway in hypoxic–ischemic neonatal rats

Chen,

Wei

et al. 2023

CNS Neurosci Ther

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AimsDexmedetomidine (DEX) has been reported to alleviate hypoxic–ischemic brain damage (HIBD) in neonates. This study aimed to investigate whether DEX improves cognitive impairment by promoting hippocampal neurogenesis via the BDNF/TrkB/CREB signaling pathway in neonatal rats with HIBD.MethodsHIBD was induced in postnatal day 7 rats using the Rice‐Vannucci method, and DEX (25 μg/kg) was administered intraperitoneally immediately after the HIBD induction. The BDNF/TrkB/CREB pathway was regulated by administering the TrkB receptor antagonist ANA‐12 through intraperitoneal injection or by delivering adeno‐associated virus (AAV)‐shRNA‐BDNF via intrahippocampal injection. Western blot was performed to measure the levels of BDNF, TrkB, and CREB. Immunofluorescence staining was utilized to identify the polarization of astrocytes and evaluate the levels of neurogenesis in the dentate gyrus of the hippocampus. Nissl and TTC staining were performed to evaluate the extent of neuronal damage. The MWM test was conducted to evaluate spatial learning and memory ability.ResultsThe levels of BDNF and neurogenesis exhibited a notable decrease in the hippocampus of neonatal rats after HIBD, as determined by RNA‐sequencing technology. Our results demonstrated that treatment with DEX effectively increased the protein expression of BDNF and the phosphorylation of TrkB and CREB, promoting neurogenesis in the dentate gyrus of the hippocampus in neonatal rats with HIBD. Specifically, DEX treatment significantly augmented the expression of BDNF in hippocampal astrocytes, while decreasing the proportion of detrimental A1 astrocytes and increasing the proportion of beneficial A2 astrocytes in neonatal rats with HIBD. Furthermore, inhibiting the BDNF/TrkB/CREB pathway using either ANA‐12 or AAV‐shRNA‐BDNF significantly counteracted the advantageous outcomes of DEX on hippocampal neurogenesis, neuronal survival, and cognitive improvement.ConclusionsDEX promoted neurogenesis in the hippocampus by activating the BDNF/TrkB/CREB pathway through the induction of polarization of A1 astrocytes toward A2 astrocytes, subsequently mitigating neuronal damage and cognitive impairment in neonates with HIBD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine alleviates cognitive impairment by promoting hippocampal neurogenesis via BDNF/TrkB/CREB signaling pathway in hypoxic–ischemic neonatal rats

Chen,

Wei

et al. 2023

CNS Neurosci Ther

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“…DJ-1 can compensate for PINK1 function, while DJ-1 mutations inhibit mitophagy, leading to the accumulation of obsolete mitochondria and inducing neurodegenerative lesions that, in turn, induce PD. The DJ-1 gene was up-regulated in the frontal cortex of rats after exercise, maintaining mitochondrial proteostasis and thereby delaying PD symptoms [117,118].…”

Section: Exercise Improves Pd By Modulating Mitophagymentioning

confidence: 99%

The Role of Exercise in Maintaining Mitochondrial Proteostasis in Parkinson’s Disease

Liu

et al. 2023

IJMS

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Parkinson’s disease (PD) is the second most common rapidly progressive neurodegenerative disease and has serious health and socio-economic consequences. Mitochondrial dysfunction is closely related to the onset and progression of PD, and the use of mitochondria as a target for PD therapy has been gaining traction in terms of both recognition and application. The disruption of mitochondrial proteostasis in the brain tissue of PD patients leads to mitochondrial dysfunction, which manifests as mitochondrial unfolded protein response, mitophagy, and mitochondrial oxidative phosphorylation. Physical exercise is important for the maintenance of human health, and has the great advantage of being a non-pharmacological therapy that is non-toxic, low-cost, and universally applicable. In this review, we investigate the relationships between exercise, mitochondrial proteostasis, and PD and explore the role and mechanisms of mitochondrial proteostasis in delaying PD through exercise.

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“…In the hypoxic ischemic encephalopathy rat model, endurance training preserved hippocampal and cerebral cortical mitochondrial membrane integrity to lower cytoplasmic and nuclear levels of the mitochondrial apoptosis-inducing proteins AIF and cytochrome c, as well as cleaved caspase-3. The antiapoptotic impact of exercise training improved motor function, learning, and memory suggesting that exercise training stabilizes mitochondrial function to protect against cell death in neurodegenerative disease [ 142 ].…”

Section: Interventional Strategies To Correct Dysfunctional Mqc and D...mentioning

confidence: 99%

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

Curtis

Seeds²,

Mattson

et al. 2022

Cells

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Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson’s disease (PD). The improper selection of mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. The downstream effects include oxidative damage, failure to maintain proteostasis and ion gradients, and decreased NAD+ and NADPH levels, resulting in insufficient energy metabolism and neurotransmitter synthesis. A ketosis-based metabolic therapy that increases the levels of (R)-3-hydroxybutyrate (BHB) may reverse the dysfunctional MQC by partially replacing glucose as an energy source, by stimulating mitophagy, and by decreasing inflammation. Fasting can potentially raise cytoplasmic NADPH levels by increasing the mitochondrial export and cytoplasmic metabolism of ketone body-derived citrate that increases flux through isocitrate dehydrogenase 1 (IDH1). NADPH is an essential cofactor for nitric oxide synthase, and the nitric oxide synthesized can diffuse into the mitochondrial matrix and react with electron transport chain-synthesized superoxide to form peroxynitrite. Excessive superoxide and peroxynitrite production can cause the opening of the mitochondrial permeability transition pore (mPTP) to depolarize the mitochondria and activate PINK1-dependent mitophagy. Both fasting and exercise increase ketogenesis and increase the cellular NAD+/NADH ratio, both of which are beneficial for neuronal metabolism. In addition, both fasting and exercise engage the adaptive cellular stress response signaling pathways that protect neurons against the oxidative and proteotoxic stress implicated in PD. Here, we discuss how intermittent fasting from the evening meal through to the next-day lunch together with morning exercise, when circadian NAD+/NADH is most oxidized, circadian NADP+/NADPH is most reduced, and circadian mitophagy gene expression is high, may slow the progression of PD.

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Mitochondrial Proteins Unveil the Mechanism by Which Physical Exercise Ameliorates Memory, Learning and Motor Activity in Hypoxic Ischemic Encephalopathy Rat Model

Cited by 6 publications

References 33 publications

Dexmedetomidine alleviates cognitive impairment by promoting hippocampal neurogenesis via BDNF/TrkB/CREB signaling pathway in hypoxic–ischemic neonatal rats

Dexmedetomidine alleviates cognitive impairment by promoting hippocampal neurogenesis via BDNF/TrkB/CREB signaling pathway in hypoxic–ischemic neonatal rats

The Role of Exercise in Maintaining Mitochondrial Proteostasis in Parkinson’s Disease

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

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