111,114-117 In addition, exercise increases neurogenesis in the adult hippocampus, an effect that

is dependent on increased expression of IGF-1 and VEGF.111,114 IGF-1 has also been shown to underlie the neuroprotective effects of exercise against different types of brain insults.118 In addition to the regulation of these growth factors, exercise has also been shown to influence other neuroprotective mechanisms.119 These positive, neuroprotective actions make exercise one of the key behavioral factors for protecting, or even reversing the damage that Inhibitors,research,lifescience,medical can be caused by environmental, physical, and psychological stressors, and even the susceptibility resulting from genetic vulnerabilities (see Figure 1). Glutamatergic excitotoxicity: stress, depression, and ADT Excess glutamatergic Inhibitors,research,lifescience,medical excitotoxicity

is one of the major mechanisms underlying neuronal damage and loss in the brain, and has been implicated in the pathophysiology of a variety of disorders, including those resulting from acute insult (eg, stroke induced ischemia or trauma) and neurodegenerative disorders (eg, amyotrophic lateral sclerosis, Huntington’s chorea, epilepsy, and Alzheimer’s disease.120,121 This section discusses evidence for excess glutamate in stress related mood disorders, the cellular mechanisms that contribute to glutamate Inhibitors,research,lifescience,medical excitotoxicity, and pharmacological strategies for intervention and treatment. Excess glutamate in depression and stress Abnormal glutamate levels and function have been implicated in psychiatric illnesses, Inhibitors,research,lifescience,medical including schizophrenia, anxiety, and mood disorders.122-124 Glutamatergic abnormalities have been reported in the plasma, serum, cerebrospinal fluid (CSF), and brain tissue of individuals suffering from mood disorders.123 Functional in vivo measures of glutamate content in the brain using proton magnetic resonance spectroscopy (II-MRS) show elevated glutamate levels in the occipital Vemurafenib in vivo cortex of depressed patients, although decreases have been reported in other regions.123,125 Preclinical studies also demonstrate a role for glutamate in the

Inhibitors,research,lifescience,medical actions of stress. Microdialysis studies have shown that stress increases extracellular levels of glutamate in the PFC and hippocampus,126,127 consistent with the possibility that atrophy of CA3 neurons arises in part through increased glutamate neurotransmission.128,129 This hypothesis is supported by studies demonstrating that TCL N-methyl-D-aspartic acid (NMDA) receptor antagonists attenuate stress-induced atrophy of CA3-pyramidal neurons.29,32,130 Stress or glucocorticoid treatment also increases the susceptibility to other types of neuronal insults, including excitotoxins and ischemia.129,131 There are several possible mechanisms that could contribute to the overactivation of glutamate in response to stress and in depression, including a decrease or loss of mechanisms for inactivation of glutamate.