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  • In glaucoma the primary retinal defect appears

    2023-04-12

    In glaucoma, the primary retinal defect appears in the GCL, whereas the other retinal layers appear normal (Kendell et al., 1995). In the current work, chronic elevation of IOP induced RGC apoptosis, especially in the GCL, and α2 adrenergic treatment reduced RGC apoptosis. Various studies have reported that adult RGCs are vulnerable to NMDA, inducing prompt degeneration of these ppar gamma agonist (Almasieh et al., 2012; Dong et al., 2008; Hama et al., 2006; Seki et al., 2010). We assumed that elevation of EAAT1 due to the α2 agonist resulted in decreased extracellular glutamate. In addition, α2 adrenergic treatment suppressed NMDA receptor expression. Our findings suggest that topical brimonidine application may affect the glutamate excitotoxicity at least partly by modulation of glutamate transporter and NMDA receptor in chronic ocular hypertension model, in addition to lowering IOP.
    Acknowledgments This work was supported by Allergan (Irvine, CA, USA). The authors have declared that no competing interests exist with the commercial funder. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
    Introduction
    Dopamine regulation of the peripheral immune system Peripheral dopamine has several different sources. The human gastrointestinal tract is reported to be a significant source of peripheral dopamine (Eisenhofer et al., 1997) providing the potential for dopamine signaling on tissue-resident immune cells of the gut. Dopamine stores, dopaminergic terminals and key dopaminergic proteins such as VMAT2 have also been detected in rat spleen and thymus (Mignini et al., 2009), both of which contain developing or resident immune cells. This suggests that the sympathetic nervous system (SNS) releases dopamine into immune-resident tissue thereby creating the potential for SNS dopamine-mediated regulation of immune cells as they develop. While norepinephrine is the main neurotransmitter of the SNS, these data indicating presence of dopaminergic stores, vesicles, and endogenous receptors support the idea that peripheral dopamine system might be involved in the regulation of biological responses and potentially regulation of peripheral immune system.
    DAT regulation of dopamine metabolism and signaling The complexity of dopamine’s effects on immune cells suggests that the peripheral dopaminergic tone is strictly regulated in order to coordinate a proper immune response. In the CNS, DAT is the principle regulator of dopaminergic tone. Human lymphocytes have been found to express both DAT and VMAT2 with the former localizing largely at the plasma membrane and the latter in various cellular locations (Amenta et al., 2001). Intriguingly, similar to DAT function in the CNS, DAT in peripheral lymphocytes displays a Michaelis-Menten-like uptake kinetic profile in a sodium-chloride and temperature-dependent manner (Faraj et al., 1995). Additionally, cocaine, which is a DAT blocker and binds to a site that overlaps with the dopamine binding site on the DAT molecule, was shown to inhibit the DAT-dependent dopamine uptake into lymphocytes in a dose-dependent manner (Faraj et al., 1995, Beuming et al., 2008). This body of evidence suggests that DAT expressed in peripheral lymphocytes is functionally similar to DAT studied in heterologous system and dopamine neurons, implying that DAT on immune cells plays a role in modulating peripheral dopaminergic tone and may also abide by established regulatory mechanisms. It should be noted that over the last two decades, the DAT biology has been primarily studied in the HEK, CHO or PC12 cells expressing the transporter. Therefore, it is likely that some of the regulatory mechanisms described for DAT are shared amongst most DAT-expressing cells, including peripheral immune cells. We therefore review the literature on DAT regulation as established in both heterologous system and neurons.