This is just a partial listing of the signal transduction cascades and factors that could contribute to antidepressant regulation of adult neurogenesis. Targets for regulation of the cAMP-CREB cascade There are several different sites within

the cAMP pathway that could be targeted for drug development. One that has already proven to be effective for antidepressant treatment is blockade of PDE4 and the breakdown of cAMP. Rolipram is a PDF’4-selective inhibitor that has Inhibitors,research,lifescience,medical been demonstrated to have antidepressant efficacy in early clinical trials and behavioral models of depression.69,70 However, the clinical use of rolipram has been limited by its side effects, primarily nausea. The identification of four different. PDE4 isozymes Inhibitors,research,lifescience,medical that are equally inhibited by rolipram raises the possibility that one of the isozymes underlies the antidepressant actions of rolipram, while another mediates its side effects. Studies are currently under way to characterize the regional distribution and function Inhibitors,research,lifescience,medical of the three PDE4 isozymes expressed in brain (PDE4A, PDE4B, and PDE4D) and the role of these isozymes in the actions of antidepressant treatment.71 Studies of mutant mice demonstrate that null mutation of PDE4D produces an antidcpressant-like

phenotype indicating Inhibitors,research,lifescience,medical a role for this isozyme,72 and similar studies are currently under way for PDE4A and PDE4B. BDNF as a target for drug development The use of BDNF and other neurotrophic factors

for the treatment of neurological disorders has been a subject of interest, for several years, although problems with delivery, efficacy, and side effects have hampered these efforts. To more directly replicate the in vivo situation, it may be possible to stimulate the expression of endogenous BDNF expression by stimulating signaling pathways known to regulate this neurotrophic factor. First, Inhibitors,research,lifescience,medical activation of the cAMP-CREB cascade by inhibition of PDE4 increases the expression of BDNF.56 Small molecular agonists for neurotransmitter receptors have also exhibited Phosphatidylinositol diacylglycerol-lyase some promise. Activation of ionotropic glutamate receptors increases BDNF expression and could be targeted for the treatment of depression.73 One drug that modulates glutamate transmission and increases BDNF expression is memantine.74 Riluzole, a. sodium channel blocker, also increases BDNF expression, as well as neurogenesis in adult hippocampus.75 Specific 5-HT and norepinephrine receptor subtypes that Barasertib research buy activate cAMP (eg, β-adrenergic, 5-HT7), Ca2+, or mitogen-activated protein kinase (α1-adrenergic, 5-HT1A) pathways could also be targets for development.