Na K ATPase adenosine triphosphate ATP

Na+/K+-ATPase, tranylcypromine sale and astrocytic glutamate transporters act together to maintain sodium and potassium gradients and the proper activities of EAAT1 and EAAT2 (Rose et al., 2009; Sheean et al., 2013); nevertheless, in present study, Na+/K+-ATPase activity was shown to be increased as from 24 h. It is possible to suggest that such augmented activity is a compensatory mechanism to reduce the extracellular potassium content and to decrease the electrical stimulation caused by the changes in electrolytes distribution (Kinjo et al., 2007; Yang et al., 1994). Moreover, glycolytic enzymes and mitochondria are also required to support astrocytic glutamate uptake (Genda et al., 2011; Sheean et al., 2013). Genda et al. (2011) demonstrated that either glycolysis or oxidative phosphorylation are sufficient to support transport, but when both are inhibited, glutamate transport is severely compromised (Genda et al., 2011). Thus, it is possible that the acute energetic demand imposed after the event caused the partial inhibition of EAAT1 and EAAT2, whereas the augmented Na+/K+-ATPase activity could be partially responsible for the increased EAAT2 expression. An increase of EAAT2 is reported to exert significant neuroprotective effects 7 days after focal cerebral ischemia (Fontana, 2015; Harvey et al., 2011). Yatomi et al. (2013) showed that chronic cerebral hypoperfusion resulted in a transient up-regulation of glial glutamate transporter EAAT2 (Yatomi et al., 2013). Likewise, several reports show distinct changes in the EAAT's expression patterns according to the protocol of brain lesion (Martinez-Lozada et al., 2016; Sánchez-Mendoza et al., 2010). The ROCK/Rho system seems to play a major role in determining the cell surface expression of EAAT1/2 and interfere with astrocytic morphology, contractility, migration, proliferation and survival (Lau et al., 2011; Pellegrin and Mellor, 2007; Riento and Ridley, 2003). Therefore, considering the diversity of aforementioned results, the differential contribution of EAAT1 and EAAT2 expression to brain ischemia remains to be elucidated.
It is widely believed that the dysfunction of glutamate transmission participates in the etiology of a number of neurodegenerative and neuropsychiatric disorders and diseases. In the mammalian central nervous system, the excitatory amino acid transporter (EAAT) family of proteins is responsible for the high-affinity sodium-dependent uptake of glutamate into both astroglial cells and neurons. Normal EAAT function is required both for the efficient termination of glutamatergic neurotransmission and clearance of glutamate from the synaptic cleft, thereby preventing excitotoxicity. Among the five recently identified subtypes of excitatory aminoacid transporters (EAAT-1–5), three of them (EAAT-1/GLAST, EAAT-2/GLT-1, and EAAT-3/EAAC1) are involved in synaptic glutamate homeostasis. Further classification distinguishes neuronal transporter EAAT-3 from glial transporters EAAT-1 and EAAT-2, with the latter being the major contributor to glutamate uptake from the synapse. An ever-growing interest in the area led to the discovery of several classes of restricted glutamate analogs as inhibitors of EAATs (pyrolidine dicarboxylates, aminocyclobutane dicarboxylates, and carboxycyclopropyl glycines). Many of these relatively compact molecules act as competitive (transportable) substrates inducing transport currents and heteroexchange. A close structural similarity of these earlier series with glutamate presents a plausible explanation for the poor selectivity across EAAT subtypes and substantial affinity to other glutamate receptors (mGluRs and iGluRs). Finally, their use as pharmacological tools is also affected by modest micromolar potency and poor physico-chemical properties. While more recently designed non-transportable ligands, such as dl--β-hydroxyaspartate and its benzylated derivative (TBOA), and the novel heptane dicarboxylate-3-amino-tricyclo[2.2.1.0]heptane-1,3-dicarboxylic acid offered improved potency, they still fall short of being ideal tool molecules. The latest generation of TBOA-based analogs delivers nanomolar potent EAAT-2 inhibitors (measured in transfected MDCK cells), with the most selective agent PMB-TBOA ((2,3(S)-3-[3-(4-methoxybenzoylamino)benzyloxy]aspartate) exhibiting a 39-fold selectivity over EAAT3. Manifesting a notably better profile, this series still leaves room for improvement in selectivity and physico-chemical properties.