Amantadine Attenuated Hypoxia-Induced Mitochondrial Oxidative Neurotoxicity, Apoptosis, and Inflammation via the Inhibition of TRPM2 and TRPV4 Channels

Öcal, Özgür; Coşar, Aymer; Nazıroğlu, Mustafa

doi:10.1007/s12035-022-02814-6

Cited by 9 publications

(6 citation statements)

References 55 publications

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“…Basing on the reports that overactive TRPV4, a Ca 2+ ‐permeable nonselective cation channel, has been associated to Ca 2+ influx overload, increased generation of mROS, and mitochondrial dysfunction in liver diseases and neurotoxicity (Hong et al, 2016; Öcal et al, 2022; Özşimşek & Nazıroğlu, 2021; Zhang et al, 2017), we hypothesized that the SMG‐induced Ca 2+ overload in ROBs may be caused by altered activity or expression level of TRPV4. To verify this hypothesis, the expression levels of TRPV4 in ROBs were examined by western blot analysis after different time of exposure to SMG.…”

Section: Resultsmentioning

confidence: 99%

Simulated microgravity‐induced oxidative stress and loss of osteogenic potential of osteoblasts can be prevented by protection of primary cilia

Miao,

Liu,

Sun

et al. 2023

Journal Cellular Physiology

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Oxidative stress has been considered to be closely related to spaceflight‐induced bone loss; however, mechanism is elusive and there are no effective countermeasures. Using cultured rat calvarial osteoblasts exposed to microgravity simulated by a random positioning machine, this study addressed the hypotheses that microgravity‐induced shortening of primary cilia leads to oxidative stress and that primary cilium protection prevents oxidative stress and osteogenesis loss. Microgravity was found to induce oxidative stress (as represented by increased levels of reactive oxygen species (ROS) and malondialdehyde production, and decreased activities of antioxidant enzymes), which was perfectly replicated in osteoblasts growing in NG with abrogated primary cilia (created by transfection of an interfering RNA), suggesting the possibility that shortening of primary cilia leads to oxidative stress. Oxidative stress was accompanied by mitochondrial dysfunction (represented by increased mitochondrial ROS and decreased mitochondrial membrane potential) and intracellular Ca2+ overload, and the latter was found to be caused by increased activity of Ca2+ channel transient receptor potential vanilloid 4 (TRPV4), as also evidenced by TRPV4 agonist GSK1016790A‐elicited Ca2+ influx. Supplementation of HC‐067047, a specific antagonist of TRPV4, attenuated microgravity‐induced mitochondrial dysfunction, oxidative stress, and osteogenesis loss. Although TRPV4 was found localized in primary cilia and expressed at low levels in NG, microgravity‐induced shortening of primary cilia led to increased TRPV4 levels and Ca2+ influx. When primary cilia were protected by miR‐129‐3p overexpression or supplementation with a natural flavonoid moslosooflavone, microgravity‐induced increased TRPV4 expression, mitochondrial dysfunction, oxidative stress, and osteogenesis loss were all prevented. Our data revealed a new mechanism that primary cilia function as a controller for TRPV4 expression. Microgravity‐induced injury on primary cilia leads to increased expression and overactive channel of TRPV4, causing intracellular Ca2+ overload and oxidative stress, and primary cilium protection could be an effective countermeasure against microgravity‐induced oxidative stress and loss of osteogenic potential of osteoblasts.

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Section: Resultsmentioning

confidence: 99%

Simulated microgravity‐induced oxidative stress and loss of osteogenic potential of osteoblasts can be prevented by protection of primary cilia

Miao,

Liu,

Sun

et al. 2023

Journal Cellular Physiology

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“…Amantadine appears to act as a NMDA and indirect dopamine agonist [ 189 ]. A recent study found that amantadine has some effects on Ca 2+ fluxes in brain cells, facilitated by transient receptor potential cation channel subfamily V member 4 (TRPV4) and transient receptor potential cation channel subfamily M member 2 (TRPM2) [ 190 ]. TRPV4 encodes for a Ca 2+ -permeable, nonselective cation channel involved in the regulation of systemic osmotic pressure by the brain [ 190 , 191 , 192 ].…”

Section: Therapeutic Intervention For Recovery From Traumatic Brain I...mentioning

confidence: 99%

“…A recent study found that amantadine has some effects on Ca 2+ fluxes in brain cells, facilitated by transient receptor potential cation channel subfamily V member 4 (TRPV4) and transient receptor potential cation channel subfamily M member 2 (TRPM2) [ 190 ]. TRPV4 encodes for a Ca 2+ -permeable, nonselective cation channel involved in the regulation of systemic osmotic pressure by the brain [ 190 , 191 , 192 ]. TRPM2 is a non-selective calcium-permeable cation channel of the Transient Receptor Potential ion channel superfamily thought to play a role in bipolar affective disorder [ 191 ] and in neuroblastoma [ 192 ].…”

Section: Therapeutic Intervention For Recovery From Traumatic Brain I...mentioning

confidence: 99%

“…TRPM2 is a non-selective calcium-permeable cation channel of the Transient Receptor Potential ion channel superfamily thought to play a role in bipolar affective disorder [ 191 ] and in neuroblastoma [ 192 ]. It has been demonstrated that amantadine can reduce hypoxia-mediated mitochondria ROS, apoptosis, and TRPM2/TRPV4-mediated overload Ca 2+ influx [ 190 ]. It has been reported to be neuroprotective in neurodegenerative and cerebrovascular diseases associated with the upregulation of mitochondrial ROS, Ca 2+ , and Zn 2+ concentration [ 190 ].…”

Section: Therapeutic Intervention For Recovery From Traumatic Brain I...mentioning

confidence: 99%

“…It has been demonstrated that amantadine can reduce hypoxia-mediated mitochondria ROS, apoptosis, and TRPM2/TRPV4-mediated overload Ca 2+ influx [ 190 ]. It has been reported to be neuroprotective in neurodegenerative and cerebrovascular diseases associated with the upregulation of mitochondrial ROS, Ca 2+ , and Zn 2+ concentration [ 190 ]. Zolpidem is a hypnotic drug targeting a specific site of the GABA-A receptor, and it is considered a therapeutic choice in disorders of consciousness [ 193 ].…”

Section: Therapeutic Intervention For Recovery From Traumatic Brain I...mentioning

confidence: 99%

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Imbalance of Essential Metals in Traumatic Brain Injury and Its Possible Link with Disorders of Consciousness

Squitti

Reale

Tondolo

et al. 2023

IJMS

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Dysfunction of the complex cerebral networks underlying wakefulness and awareness is responsible for Disorders of Consciousness (DoC). Traumatic Brain Injury (TBI) is a common cause of DoC, and it is responsible for a multi-dimensional pathological cascade that affects the proper functioning of the brainstem and brain consciousness pathways. Iron (Fe), Zinc (Zn), and Copper (Cu) have a role in the neurophysiology of both the ascending reticular activating system, a multi-neurotransmitter network located in the brainstem that is crucial for consciousness, and several brain regions. We aimed to summarize the role of these essential metals in TBI and its possible link with consciousness alterations. We found that TBI alters many neuronal molecular mechanisms involving essential metals, causing neurodegeneration, neural apoptosis, synaptic dysfunction, oxidative stress, and inflammation. This final pattern resembles that described for Alzheimer’s disease (AD) and other neurological and psychiatric diseases. Furthermore, we found that amantadine, zolpidem, and transcranial direct current stimulation (tDCS)—the most used treatments for DoC recovery—seem to have an effect on essential metals-related pathways and that Zn might be a promising new therapeutic approach. This review summarizes the neurophysiology of essential metals in the brain structures of consciousness and focuses on the mechanisms underlying their imbalance following TBI, suggesting their possible role in DoC. The scenario supports further studies aimed at getting a deeper insight into metals’ role in DoC, in order to evaluate metal-based drugs, such as metal complexes and metal chelating agents, as potential therapeutic options.

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Cerebral Hypoxia-Induced Molecular Alterations and Their Impact on the Physiology of Neurons and Dendritic Spines: A Comprehensive Review

Cui,

Jiang,

Wang

et al. 2024

Cell Mol Neurobiol

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This article comprehensively reviews how cerebral hypoxia impacts the physiological state of neurons and dendritic spines through a series of molecular changes, and explores the causal relationship between these changes and neuronal functional impairment. As a severe pathological condition, cerebral hypoxia can significantly alter the morphology and function of neurons and dendritic spines. Specifically, dendritic spines, being the critical structures for neurons to receive information, undergo changes such as a reduction in number and morphological abnormalities under hypoxic conditions. These alterations further affect synaptic function, leading to neurotransmission disorders. This article delves into the roles of molecular pathways like MAPK, AMPA receptors, NMDA receptors, and BDNF in the hypoxia-induced changes in neurons and dendritic spines, and outlines current treatment strategies. Neurons are particularly sensitive to cerebral hypoxia, with their apical dendrites being vulnerable to damage, thereby affecting cognitive function. Additionally, astrocytes and microglia play an indispensable role in protecting neuronal and synaptic structures, regulating their normal functions, and contributing to the repair process following injury. These studies not only contribute to understanding the pathogenesis of related neurological diseases but also provide important insights for developing novel therapeutic strategies. Future research should further focus on the dynamic changes in neurons and dendritic spines under hypoxic conditions and their intrinsic connections with cognitive function.

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Amantadine Attenuated Hypoxia-Induced Mitochondrial Oxidative Neurotoxicity, Apoptosis, and Inflammation via the Inhibition of TRPM2 and TRPV4 Channels

Cited by 9 publications

References 55 publications

Simulated microgravity‐induced oxidative stress and loss of osteogenic potential of osteoblasts can be prevented by protection of primary cilia

Simulated microgravity‐induced oxidative stress and loss of osteogenic potential of osteoblasts can be prevented by protection of primary cilia

Imbalance of Essential Metals in Traumatic Brain Injury and Its Possible Link with Disorders of Consciousness

Cerebral Hypoxia-Induced Molecular Alterations and Their Impact on the Physiology of Neurons and Dendritic Spines: A Comprehensive Review

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