One possible pathway summarizing the overall action involves

One possible pathway summarizing the overall action involves NMDA receptor activation – Ca2+ influx – protein kinase A (PKA) activation – ERK phosphorylation and subsequent synaptic plasticity (Thomas and Huganir, 2004). A few studies have also shown modulation of synaptic glutamate transporters in the brain by estrogen, although both enhancement (Keller et al., 1997, Liang et al., 2002) and inhibition (Sato et al., 2003) of glutamate uptake have been reported. These findings suggest high-affinity glutamate transporters as potential therapeutic targets for chronic pain states that tend to fluctuate over the female cycle. Pharmacological strategies to up-regulate EAAT function e.g. riluzole; ceftriaxone and valproate can potentially alleviate pain in certain chronic pain conditions. However, a human trial failed to show the efficacy of riluzole in chronic neuropathic pain (Galer et al., 2000). Interestingly there have been some reports of its efficacy in visceral pain states such as IBS (Mishra et al., 2014). Our data would suggest that care is needed as to when its efficacy may be most potent across the menstrual cycle in females.
Conclusions
Competing interests
Acknowledgments All authors were involved in the research or preparation of the manuscript. The APC Microbiome Institute is funded by Science Foundation Ireland (SFI), through the Irish Government’s National Development Plan. John F. Cryan is supported by SFI (grant no is 07/CE/B1368 and 12/RC/2273). John F. Cryan is also supported by the Irish Health Research Board, Health Research Awards (HRA_POR/2011/23) and (HRA_POR/2012/32).
Introduction Stroke is the major cause of disability in middle and late life resulting in severe neuronal degeneration and loss of brain functions. The ischemic insult leads to situations involving energy failure where the glutamate transport is impaired and high levels of this amino Betamethasone are accumulated on the synaptic cleft (Thomazi et al., 2008). Then, glutamate can activate NMDA, AMPA or mGluR1 receptors, contributing to the brain damage (Meldrum, 2000). High-affinity excitatory amino acid transporters (EAATs) reuptake the glutamate released in the synapses against its concentration gradient, thus terminating its excitatory action and maintaining it below neurotoxic levels (Tzingounis and Wadiche, 2007). Furthermore, EAATs are responsible for shuttling glutamate into cells needing this amino acid as a precursor (Berger and Hediger, 1998). Several EAATs have been isolated and characterized, namely l-glutamate/l-aspartate transporter (GLAST) (Storck et al., 1992), glial glutamate transporter 1 (GLT-1) (Pines et al., 1992), excitatory amino acid carrier-1 (EAAC1) (Kanai and Hediger, 1992), and excitatory amino acid transporters 4 and 5 (EAAT4 and EAAT5 respectively) (Fairman et al., 1995, Arriza et al., 1997). GLT-1, GLAST and EAAC1 are widely distributed in the central nervous system (Rothstein et al., 1994, Lehre et al., 1995), while EAAT4 and EAAT5 are mostly restricted to cerebellum (Yamada et al., 1996) and retina (Arriza et al., 1997) respectively. EAAC1 mRNA is predominantly located in neurons (Rothstein et al., 1994). Two alternate splicing of GLAST, GLAST1a and GLAST1b, have been described. GLAST1a is expressed in glial cells (Macnab et al., 2006) while GLAST1b appears to be expressed in the plasma membranes of populations of apparently abnormal neurons (Macnab and Pow, 2007). GLT-1 mRNA exists in multiple splice variants, some of which are translated into variant proteins and at least 5 variants are expressed in the astrocytic cultures from different brain areas (Rozyczka and Engele, 2005). Immunoreactivity of three of these variants that present differences in the C terminus (GLT-1a, b and c) shows that in 8-week-old rats GLT-1a represents 90%, GLT-1b 6% and GLT-1c 1% of total hippocampal GLT-1 and it has been hypothesized that the expression of these variants may represent the activities of different regulatory pathways (Berger et al., 2005, Holmseth et al., 2009, Rauen et al., 2004).