Glutamate is one of the most prevalent neurotransmitters released by excitatory neurons in the central nervous system (CNS); however, residual glutamate in the extracellular space is, potentially, neurotoxic. It is now well-established that one of the fundamental functions of astrocytes is to uptake most of the synaptically-released glutamate, which optimizes neuronal functions and prevents glutamate excitotoxicity. In the CNS, glutamate clearance is mediated by glutamate uptake transporters expressed, principally, by astrocytes. Interestingly, recent studies demonstrate that extracellular glutamate stimulates Ca²⁺ release from the astrocytes’ intracellular stores, which triggers glutamate release from astrocytes to the adjacent neurons, mostly by an exocytotic mechanism. This released glutamate is believed to coordinate neuronal firing and mediate their excitatory or inhibitory activity. Therefore, astrocytes contribute to glutamate homeostasis in the CNS, by maintaining the balance between their opposing functions of glutamate uptake and release. This dual function of astrocytes represents a potential therapeutic target for CNS diseases associated with glutamate excitotoxicity. In this regard, we summarize the molecular mechanisms of glutamate uptake and release, their regulation, and the significance of both processes in the CNS. Also, we review the main features of glutamate metabolism and glutamate excitotoxicity and its implication in CNS diseases.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein–coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.

Inflammation is a crucial factor in the pathogenesis of numerous diseases. This study sought to evaluate the effects of thymol and carvacrol, the main components of Thymus vulgaris (thyme) essential oil, on transcription factors regulating inflammation. Lipopolysaccharide (LPS)-stimulated J774.1 mouse macrophages were examined by real time-PCR for interleukin (IL)-1β and tumor necrosis factor (TNF)-α gene expression in the presence of these compounds. Levels of inducible phospho-nuclear factor-κB (pNF-κB) p65, activator protein-1 [AP-1(c-Fos/c-Jun)], and nuclear factors of activated T-cells (NFATs) were also measured using Western blots. Levels of phosphorylation of stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinase (SAPK/JNK), signal transducer, and activator of transcription (STAT-3), p38, IκBα, and NF-κB p65, as well as total levels of IL-1β and TNFα were determined. The results indicated carvacrol significantly reduced both IL-1β and TNFα at the protein and mRNA levels; thymol also significantly reduced IL-1β expression. Western blot analyses of nuclear cell extracts revealed both agents caused significantly decreased expression of c-Fos, NFAT-1, and NFAT-2; decreased expression of c-Jun was only caused by carvacrol. Neither agent inhibited p-NF-κB p65 expression. At the protein level, carvacrol and thymol each caused decreases in inducible phospho-SAPK/JNK and phospho-STAT3 levels, whereas only carvacrol resulted in increased p-p38 levels in the total cell extract. Despite the reduction of phospho-IκBα caused by both agents, p-NF-κB p65 still increased in the presence of carvacrol. Based on these findings, it is concluded that carvacrol and thymol could contribute to reduction of inflammatory responses through modulation of the expression of JNK, STAT-3, AP-1, and NFATs.