MCT4-Mediated Expression of EAAT1 is Involved in the Resistance to Hypoxia Injury in Astrocyte–Neuron co-Cultures

Abstract

Hypoxic stressors contribute to neuronal death in many brain diseases. Astrocyte processes surround most neurons and are therefore anatomically well-positioned to shield them from hypoxic injury. Excitatory amino acid transporters (EAATs), represent the sole mechanism of active reuptake of glutamate into the astrocytes and neurons and are essential to dampen neuronal excitation following glutamate release at synapses. Glutamate clearance impairment from any factors is bound to result in an increase in hypoxic neuronal injury. The brain energy metabolism under hypoxic conditions depends on monocarboxylate transporters (MCTs) that are expressed by neurons and glia. Previous co-immunoprecipitation experiments revealed that MCT4 directly modulate EAAT1 in astrocytes. The reduction in both surface proteins may act synergistically to induce neuronal hyperexcitability and excitotoxicity. Therefore we hypothesized that astrocytes would respond to hypoxic conditions by enhancing their expression of MCT4 and EAAT1, which, in turn, would enable them to better support neurons to survive lethal hypoxia injury. An oxygen deprivation (OD) protocol was used in primary cultures of neurons, astrocytes, and astrocytes-neurons derived from rat hippocampus, with or without MCT4-targeted short hairpin RNA (shRNA) transfection. Cell survival, expression of MCT4, EAAT1, glial fibrillary acidic protein and neuronal nuclear antigen were evaluated. OD resulted in significant cell death in neuronal cultures and up-regulation of MCT4, EAAT1 expression respectively in primary cell cultures, but no injury in neuron-astrocyte co-cultures and astrocyte cultures. However, neuronal cell death in co-cultures was increased exposure to shRNA-MCT4 prior to OD. These findings demonstrate that the MCT4-mediated expression of EAAT1 is involved in the resistance to hypoxia injury in astrocyte-neuron co-cultures.

Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice

“…Because increased accumulation of lipid content in aging SkM could cause progressive sarcopenia (30), the mRNA profile of these genes as induced by dietary epicatechin is noteworthy. In addition, epicatechin-reversed expression of the high-affinity glutamate transporter Slc1a3 , or EAAT1 , was shown to promote resistance to hypoxic injury in astrocyte-neuron cocultures (50); this finding may be relevant to cellular processes of the neuromuscular junction (51) and hence overall SkM function.…”

Cytoprotection against Hypoxic and/or MPP+ Injury: Effect of δ–Opioid Receptor Activation on Caspase 3

“…Furthermore, as the morbidity of PD is greater among older people, it might be associated with age-related conditions such as prolonged ischemia or hypoxia in the brain. There is ample evidence to show that an insufficient blood or oxygen supply to the brain, could attenuate neurons’ resistance to environmental damage, and it can even trigger cell death [5,6,7]. Therefore, hypoxia/ischemia and neurotoxins should also be recognized as critical pathogenic factors that contribute to the development of PD.…”

Transcriptome Analysis Identifies Key Metabolic Changes in the Hooded Seal (Cystophora cristata) Brain in Response to Hypoxia and Reoxygenation

“…Previous studies suggested that Mcts are involved in the response to hypoxia and ischemia. For example, hypoxic preconditioning caused an upregulation of Mct4 in rat astrocytes [45] and a knockdown of Mct4 interfered with the survival of mixed astrocyte-neuron cultures under hypoxia [46]. Mct4 activity and structure appear to be associated to the astrocyte-specific excitatory amino acid transporter 1 (Eaat1) [47].…”