Interestingly, BDNF itself also possesses antidepressant-like effects in rodent models used to screen antidepressants following direct infusion into either the midbrain136 or hippocampus.137 This enhancement in BDNF by antidepressants may help promote mechanisms of neuronal protection and survival key to reducing stress-induced damage. Antidepressants have also been found to have neuroprotective effects. Inhibitors,research,lifescience,medical For instance, the SSRI fluoxetine prevented the neurotoxic effects of ecstasy (3,4-methylenedioxymethamphetamine, MDMA).138,139 Mechanistically, fluoxetine’s neuroprotective effects, in addition to restoring serotonin levels, may
result from activation of p38 MAPK, BDNF, and GDNF.140 MAOIs (eg, pargyline, nialamide, Inhibitors,research,lifescience,medical tranylcypromine) inhibiting both MAO-A and MAO-B protected
against l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine (MPTP)induced dopaminergic neural toxicity.141 Interestingly, Ladostigil, a MAOI used to treat both depression and neurodegeneration that has promising neuroprotective effects, reportedly activated Bcl-2 Inhibitors,research,lifescience,medical family members and BDNF142 in addition to ERK1/2 (p44/42 MAPK).143 Notably, exercise also possesses neuroprotective effects. Carro and colleagues showed that rodents subjected to treadmill running were protected against various insults ranging from treatment with the neurotoxin domoic acid to inherited neurodegeneration affecting Purkinje cells of the cerebellum.144 These protective effects depended Inhibitors,research,lifescience,medical in part on the find more neurotrophic factor insulin-like growth factor I (IGF-1); infusing a blocking anti-IGF-1 antibody reduced the protective effects of exercise. Effects of antidepressants on neurogenesis in animals Antidepressants increase hippocampal
Inhibitors,research,lifescience,medical adult neurogenesis following chronic but not acute treatment. Chronic treatment with the SSRI fluoxetine, the MAOI tranylcypromine, or the SNRI reboxetine produced an approximately 20% to 40% increase in bromodeoxyuridine BrdU-labeled hippocampal cells145; at least 2 weeks of fluoxetine treatment was required to enhance neurogenesis. Furthermore, while stress decreases hippocampal neurogenesis, chronic antidepressant before treatment prevented these stress-induced changes.146,147 ECT also increased neurogenesis in rodents,148 as well as hippocampal synapse number.149 ECT was similarly found to increase neurogenesis in nonhuman primates,150 and exercise increased hippocampal neurogenesis151 in addition to enhancing hippocampal-dependent learning and long-term potentiation (LTP).151 The molecular mechanisms underlying these antidepressant-induced enhancements in neurogenesis may involve the MAPK/ERK and/or Wnt/GSK-3 pathways. A very recent study found that suppression of the gene disrupted in schizophrenia 1 (DISCI), which has been implicated in BPD, major depressive disorder (MDD), and schizophrenia, decreased neurogenesis by acting through GSK3β.