Epigallocatechin-3-Gallate Ameliorated Iron Accumulation and Apoptosis and Promoted Neuronal Regeneration and Memory/Cognitive Functions in the Hippocampus Induced by Exposure to a Chronic High-Altitude Hypoxia Environment

Abstract

We aimed to explore the protective effects and potential treatment mechanism of Epigallocatechin-3-gallate (EGCG) in an animal model of chronic exposure in a natural high-altitude hypoxia (HAH) environment. Behavioral alterations were assessed with the Morris water maze test. Iron accumulation in the hippocampus was detected by using DAB enhanced Perls’ staining, MRI, qPCR and colorimetry, respectively. Oxidative stress (malondialdehyde, MDA), apoptosis (Caspase-3), and neural regeneration (brain-derived neurotrophic factor, BDNF) were detected by using ELISA and western blotting. Neural ultrastructural changes were evaluated by transmission electron microscopy (TEM). The results showed that learning and memory performance of rats decreased when exposure to HAH environment. It was followed by iron accumulation, dysfunctional iron metabolism, reduced BDNF and the upregulation of MDA and Caspase-3. TEM confirmed the ultrastructural changes in neurons and mitochondria. EGCG reduced HAH-induced cognitive impairment, iron deposition, oxidative stress, and apoptosis and promoted neuronal regeneration against chronic HAH-mediated neural injury.

Effect of Epigallocatechin-3-gallate on Stress-Induced Depression in a Mouse Model: Role of Interleukin-1β and Brain-Derived Neurotrophic Factor

“…These results are in line with previous studies [ 77 – 79 ], indicating that CA3 area is vulnerable to stress. In addition, in our research, we found that EGCG relieved the CA3 neuronal disorders in CUMS mice, corroborating earlier reports exploring the beneficial role of EGCG against neurodegenerative structural changes in the hippocampus [ 80 , 81 ]. It has also been shown that in vitro administration of 0.5 µM EGCG may be effective in promoting axonal regeneration in cultured CNS cells and blocking the antineuritogenic activity of myelin-derived inhibitors [ 82 ].…”

High-Altitude Hypoxia Exposure Induces Iron Overload and Ferroptosis in Adipose Tissue

“…Studies have shown that HA exposure elicits remarkable alterations in iron metabolism, leading to disturbances in iron homeostasis and giving rise to toxicities such as inflammation, oxidative stress, and ferroptosis [ 7 , 8 , 9 , 10 , 12 ]. Yet, as far as we know, no relevant study has examined these effects on adipose tissue during HA treatment.…”

“…However, iron contents need to be precisely regulated, as excess iron can exert toxicity by the Fenton reaction to produce powerful ROS, inducing oxidative damage [ 2 ]. Previous studies have shown that long-lasting HA hypoxia significantly increased brain iron concentrations, especially in deep gray matter regions, inducing cognitive impairment and neural injury [ 7 , 9 ]. We investigated the changes in iron levels by iron staining and colorimetry in adipose tissue as a result of HA exposure.…”

“…Iron homeostasis is vital to health and is maintained in a balanced state under normal conditions [ 6 ]. However, numerous studies revealed that HA hypoxia exposure induced significant changes in iron metabolism (uptake, storage, and efflux), causing iron homeostasis imbalance and even leading to toxicities such as oxidative stress [ 7 , 8 , 9 ], inflammatory response [ 10 , 11 ], and ferroptosis [ 12 ], an iron-dependent programmed cell death marked by ROS accumulation. As reported, chronic HA hypoxia causes brain iron accumulation and dysfunctional iron metabolism, inducing oxidative stress and apoptosis, and ultimately triggering cognitive impairment [ 7 ].…”

Hippocampal adaptation to high altitude: a neuroanatomic profile of hippocampal subfields in Tibetans and acclimatized Han Chinese residents

“…As we recruited a sample of lowlanders who migrated to high altitude for longer than 2 years, the effect of their acclimatization to hypoxia could further normalize hippocampal alterations under hypoxia. For example, in rats, accumulation was found to promote neuronal regeneration together with memory/cognitive function recovery in the hippocampus during exposure to a chronic high-altitude hypoxic environment (Chen et al, 2022 ). Another possible explanation is that the effect of hypoxia on hippocampal neurons could be complex.…”