Memantine ameliorates cognitive impairment induced by exposure to chronic hypoxia environment at high altitude by inhibiting excitotoxicity

Memantine is a non-competitive antagonist of glutamatergic NMDA receptor that is mainly used in the treatment of Alzheimer's disease. The excitatory toxicity mediated by glutamate via glutamatergic receptor signals is considered to be one of the mechanisms mediating neuronal injury and cognitiv...

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Published in:Life sciences (1973) 2021-04, Vol.270, p.119012, Article 119012
Main Authors: Ji, Weizhong, Zhang, Yaqing, Luo, Junming, Wan, Yaqi, Liu, Jie, Ge, Ri-Li
Format: Article
Language:English
Subjects:
Altitude
Altitude Sickness - drug therapy
Altitude Sickness - metabolism
Alzheimer Disease - drug therapy
Alzheimer's disease
Animal behavior
Animal cognition
Animal models
Animals
Apoptosis
Cell death
Cell Death - drug effects
Chronic hypoxic exposure
Cognition - drug effects
Cognitive ability
Cognitive Dysfunction - drug therapy
Cognitive function
Cortex (frontal)
Disease Models, Animal
Environment models
Excitatory Amino Acid Antagonists - pharmacology
Excitotoxicity
Exposure
Free radicals
Glutamate
Glutamatergic transmission
Glutamic Acid - metabolism
Glutamic acid receptors (ionotropic)
High altitude
High-altitude environments
Hippocampus - metabolism
Hypoxia
Hypoxia - metabolism
Impairment
Inhibition (psychology)
Injuries
Male
Medical treatment
Memantine
Memantine - metabolism
Memantine - pharmacology
Memory - drug effects
Molecular biology
Morphology
N-Methyl-D-aspartic acid receptors
Neurodegenerative diseases
Neurons - drug effects
Neuroprotection
Neuroprotective Agents - pharmacology
Neurotoxins - metabolism
Oxidative stress
Oxidative Stress - drug effects
Rats
Rats, Sprague-Dawley
Receptors
Receptors, N-Methyl-D-Aspartate - metabolism
Space exploration
Toxic diseases
Toxicity
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
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Summary:Memantine is a non-competitive antagonist of glutamatergic NMDA receptor that is mainly used in the treatment of Alzheimer's disease. The excitatory toxicity mediated by glutamate via glutamatergic receptor signals is considered to be one of the mechanisms mediating neuronal injury and cognitive impairment after exposure to a hypoxic environment at a high altitude. Therefore, in this study, we hypothesized that inhibiting glutamate signaling using memantine could alleviate neuronal injury and cognitive impairment in rats exposed to chronic hypoxia. we made animal models in the natural environment of the Qinghai-Tibet Plateau at an altitude of 4300 m, and used animal behavior, morphology, molecular biology and other methods to evaluate the impact of chronic hypoxia exposure on cognitive function and the neuroprotective effect of Memantine. Our results showed that the expression of NMDA receptors increased, while the expression of AMPA receptors decreased, after 4 weeks of chronic hypoxia exposure. Concomitantly, apoptotic neuronal cell death in the hippocampus and frontal cortex was significantly increased, along with levels of oxidative stress, whereas innate ability to inhibit free radicals decreased. Moreover, after 8 weeks of hypoxia exposure, learning, memory, and space exploration abilities were significantly decreased. Notably, after treatment with memantine, apoptotic neuronal cell death, oxidative stress, and free radical levels decreased, and the cognitive function of the animals improved. Present study shows that chronic hypoxia can produce the excitatory toxicity leading to neural injury and cognitive impairment that can be suppressed with memantine treatment by inhibiting excitatory toxicity. [Display omitted] •The mechanism of cognitive impairment induced by chronic hypoxic exposure is unclear.•Here, we showed that apoptotic neuronal cell death in the hippocampus and frontal cortex was significantly increased, along with levels of oxidative stress, whereas innate ability to inhibit free radicals decreased.•Notably, after treatment with memantine, apoptotic neuronal cell death, oxidative stress, and free radical levels decreased, and the cognitive function of the animals improved.•Together, our study shows that chronic hypobaric hypoxic environmental exposure can produce excitatory toxicity leading to neural injury and cognitive impairment that can be suppressed with memantine treatment by inhibiting excitatory toxicity.
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2020.119012