123 Reductions in the number or function of glia are thought to play a role in the atrophy of limbic brain regions observed in brain imaging studies, as well as decreased neuronal cell body size in postmortem brains of depressed patients.123,132,133 Recent studies demonstrate that agents that increase glial reuptake of glutamate, such as riluzole and ceftriaxone,

have antidepressant effects in rodent behavioral models and in depressed patients.132-134 Mechanisms of glutamate Inhibitors,research,lifescience,medical excitotoxicity Glutamate neurotoxicity results from excessive flux of Ca2+ via ionoptopic receptors, including AMPA, kainiate, and NMDA type receptors.120,121,123 Uncontrolled elevation of intracellular Ca2+ leads to further loss of Ca2+ buffering and homeostasis, and then to a cascade Inhibitors,research,lifescience,medical of events that contribute to cell damage and death. These include oxidative stress resulting in generation of reactive oxygen species (ROS) and nitric oxide, which results in necrotic cell death characterized by swelling, membrane damage, DNA degradation, and eventually inflammation and cell lysis.120,121,135 There are multiple sites for controlling glutamate release and activity at pre- and postsynaptic sites, as well Inhibitors,research,lifescience,medical as for buffering intracellular Ca2+ that protects against cell damage. These mechanisms are typically overcome only by severe conditions, such as

those that would occur during Adriamycin cell line stroke-induced ischemia, prolonged hypoxia, uncontrolled seizures or head trauma. As discussed above, most studies do not report a loss of neurons in post-mortem tissue from depressed patients, or in animal models. However, excess glutamate is Inhibitors,research,lifescience,medical still thought to play a

role in psychiatric illnesses, and this has resulted in targeting glutamatergic sites for development of therapeutic agents for mood disorders, as well as for other psychiatric, neurological, and neurodegenerative illnesses. Glutamate and neuroprotection: therapeutic targets Glutamate neurotransmission Inhibitors,research,lifescience,medical is controlled by a complex system of pre- and postsynaptic receptors, including ionotropic and metabotropic subtypes. In addition, regulation of tropic factor signaling cascades, including extracellular signal-related kinase (ERK), GPX6 Akt, and cAMP response element binding (CREB) can serve as neuroprotective targets for excitoxicity. There is also evidence that chronic ADT regulates the phosphorylation, trafficking, and expression of glutamate receptors, providing further evidence that the actions of ADT involves this neurotransmitter system. These topics have been extensively covered by a number of recent reviews.121,123,136,137 A brief discussion of the major glutamatergic targets will be discussed here. One of the key targets for regulation of glutamate is glial reuptake, which is the primary mechanism for inactivation of glutamate neurotransmission.