Regulation of L-Lactate in Glutamate Excitotoxicity Under Cerebral Ischemia: Pathophysiology and Preventive Strategy
Glutamate is an excitatory neurotransmitter in the central nervous system (CNS) that mediates synaptic transmission. However, glutamate homeostasis among neural cells is broken in cerebral ischemia. Excessive glutamate triggers <i>N</i>-methyl-<span style="font-variant: small-cap...
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2025-06-01
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| author | Mao Zhang Yanyan Wang Zili Gong Wen Jiang Guodong Ge Hong Guo |
| author_facet | Mao Zhang Yanyan Wang Zili Gong Wen Jiang Guodong Ge Hong Guo |
| author_sort | Mao Zhang |
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| description | Glutamate is an excitatory neurotransmitter in the central nervous system (CNS) that mediates synaptic transmission. However, glutamate homeostasis among neural cells is broken in cerebral ischemia. Excessive glutamate triggers <i>N</i>-methyl-<span style="font-variant: small-caps;">d</span>-aspartate receptors (NMDARs) in postsynaptic neurons, leading to intracellular calcium (Ca<sup>2+</sup>) overload and excitoneurotoxicity. At this moment, L-lactate may affect NMDARs and play a protective role in cerebral ischemia. This work proposes that L-lactate regulates glutamate signaling among neural cells. But, dysregulation of L-lactate in glutamate signaling cascades contributes to glutamate excitotoxicity in cerebral ischemia. In detail, L-lactate regulates the glutamine(Gln)-glutamate cycle between astrocytes and presynaptic neurons, which triggers the astroglial L-lactate-sensitive receptor (LLR)-cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, coordinating astroglial glutamate uptake and neuronal glutamate transmission. L-lactate mediates glutamate signaling and synaptic transmission among neural cells. In addition, L-lactate promotes the function of mitochondrial calcium uniporter complex (MCUC), which quickly depletes intracellular Ca<sup>2+</sup> in postsynaptic neurons. In addition, L-lactate can promote the conversion of microglia from the pro-inflammatory (M1) to anti-inflammatory (M2) phenotype. Therefore, regulation of L-lactate in glutamate signaling in the CNS might become a preventive target for cerebral ischemia. |
| format | Article |
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| institution | Kabale University |
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| publishDate | 2025-06-01 |
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| spelling | doaj-art-bcd85ebd37a44735bbb918ed7b702bf92025-08-20T03:32:15ZengMDPI AGPharmaceuticals1424-82472025-06-0118793510.3390/ph18070935Regulation of L-Lactate in Glutamate Excitotoxicity Under Cerebral Ischemia: Pathophysiology and Preventive StrategyMao Zhang0Yanyan Wang1Zili Gong2Wen Jiang3Guodong Ge4Hong Guo5Department of Medical Genetics, College of Basic Medical Science, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing 400038, ChinaDepartment of Medical Genetics, College of Basic Medical Science, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing 400038, ChinaDepartment of Neurology, Xinqiao Hospital, Army Medical University, 83 Xinqiao Main Street, Shapingba District, Chongqing 400038, ChinaDepartment of Medical Genetics, College of Basic Medical Science, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing 400038, ChinaDepartment of Medical Genetics, College of Basic Medical Science, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing 400038, ChinaDepartment of Medical Genetics, College of Basic Medical Science, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing 400038, ChinaGlutamate is an excitatory neurotransmitter in the central nervous system (CNS) that mediates synaptic transmission. However, glutamate homeostasis among neural cells is broken in cerebral ischemia. Excessive glutamate triggers <i>N</i>-methyl-<span style="font-variant: small-caps;">d</span>-aspartate receptors (NMDARs) in postsynaptic neurons, leading to intracellular calcium (Ca<sup>2+</sup>) overload and excitoneurotoxicity. At this moment, L-lactate may affect NMDARs and play a protective role in cerebral ischemia. This work proposes that L-lactate regulates glutamate signaling among neural cells. But, dysregulation of L-lactate in glutamate signaling cascades contributes to glutamate excitotoxicity in cerebral ischemia. In detail, L-lactate regulates the glutamine(Gln)-glutamate cycle between astrocytes and presynaptic neurons, which triggers the astroglial L-lactate-sensitive receptor (LLR)-cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, coordinating astroglial glutamate uptake and neuronal glutamate transmission. L-lactate mediates glutamate signaling and synaptic transmission among neural cells. In addition, L-lactate promotes the function of mitochondrial calcium uniporter complex (MCUC), which quickly depletes intracellular Ca<sup>2+</sup> in postsynaptic neurons. In addition, L-lactate can promote the conversion of microglia from the pro-inflammatory (M1) to anti-inflammatory (M2) phenotype. Therefore, regulation of L-lactate in glutamate signaling in the CNS might become a preventive target for cerebral ischemia.https://www.mdpi.com/1424-8247/18/7/935cerebral ischemiaL-lactateglutamatecalcium overloadastroglial L-lactate-sensitive receptor (LLR) |
| spellingShingle | Mao Zhang Yanyan Wang Zili Gong Wen Jiang Guodong Ge Hong Guo Regulation of L-Lactate in Glutamate Excitotoxicity Under Cerebral Ischemia: Pathophysiology and Preventive Strategy Pharmaceuticals cerebral ischemia L-lactate glutamate calcium overload astroglial L-lactate-sensitive receptor (LLR) |
| title | Regulation of L-Lactate in Glutamate Excitotoxicity Under Cerebral Ischemia: Pathophysiology and Preventive Strategy |
| title_full | Regulation of L-Lactate in Glutamate Excitotoxicity Under Cerebral Ischemia: Pathophysiology and Preventive Strategy |
| title_fullStr | Regulation of L-Lactate in Glutamate Excitotoxicity Under Cerebral Ischemia: Pathophysiology and Preventive Strategy |
| title_full_unstemmed | Regulation of L-Lactate in Glutamate Excitotoxicity Under Cerebral Ischemia: Pathophysiology and Preventive Strategy |
| title_short | Regulation of L-Lactate in Glutamate Excitotoxicity Under Cerebral Ischemia: Pathophysiology and Preventive Strategy |
| title_sort | regulation of l lactate in glutamate excitotoxicity under cerebral ischemia pathophysiology and preventive strategy |
| topic | cerebral ischemia L-lactate glutamate calcium overload astroglial L-lactate-sensitive receptor (LLR) |
| url | https://www.mdpi.com/1424-8247/18/7/935 |
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