Zhang Mao, Wang Yanyan, Gong Zili, Jiang Wen, Ge Guodong, Guo Hong
Department of Medical Genetics, College of Basic Medical Science, Army Medical University, 30 Gaotanyan Main Street, Shapingba District, Chongqing 400038, China.
Department of Neurology, Xinqiao Hospital, Army Medical University, 83 Xinqiao Main Street, Shapingba District, Chongqing 400038, China.
Pharmaceuticals (Basel). 2025 Jun 20;18(7):935. doi: 10.3390/ph18070935.
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 -methyl-d-aspartate receptors (NMDARs) in postsynaptic neurons, leading to intracellular calcium (Ca) 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 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.
谷氨酸是中枢神经系统（CNS）中的一种兴奋性神经递质，介导突触传递。然而，脑缺血时神经细胞间的谷氨酸稳态被打破。过量的谷氨酸会触发突触后神经元中的N-甲基-D-天冬氨酸受体（NMDARs），导致细胞内钙（Ca）超载和兴奋性神经毒性。此时，L-乳酸可能会影响NMDARs，并在脑缺血中发挥保护作用。这项研究提出，L-乳酸调节神经细胞间的谷氨酸信号传导。但是，L-乳酸在谷氨酸信号级联反应中的失调会导致脑缺血中的谷氨酸兴奋性毒性。具体而言，L-乳酸调节星形胶质细胞和突触前神经元之间的谷氨酰胺（Gln）-谷氨酸循环，这会触发星形胶质细胞的L-乳酸敏感受体（LLR）-环磷酸腺苷（cAMP）/蛋白激酶A（PKA）途径，协调星形胶质细胞对谷氨酸的摄取和神经元的谷氨酸传递。L-乳酸介导神经细胞间的谷氨酸信号传导和突触传递。此外，L-乳酸促进线粒体钙单向转运体复合物（MCUC）的功能，该复合物可迅速消耗突触后神经元内的Ca。此外，L-乳酸可促进小胶质细胞从促炎（M1）表型向抗炎（M2）表型的转变。因此，调节中枢神经系统中谷氨酸信号传导中的L-乳酸可能成为脑缺血的预防靶点。
