Agomelatine is a novel antidepressant acting as a melatonergic receptor agonist and serotonergic (5-HT 2C ) receptor antagonist. In adult rats, chronic agomelatine treatment enhanced cell proliferation and neurogenesis in the ventral hippocampus (VH), a region pertinent to mood disorders. This study compared the effects of agomelatine on cell proliferation, maturation, and survival and investigated the cellular mechanisms underlying these effects. Agomelatine increased the ratio of mature vs immature neurons and enhanced neurite outgrowth of granular cells, suggesting an acceleration of maturation. The influence of agomelatine on maturation and survival was accompanied by a selective increase in the levels of BDNF (brain-derived neurotrophic factor) vs those of VEGF (vascular endothelial factor) and IGF-1 (insulin-like growth factor 1), which were not affected. Agomelatine also activated several cellular signals (extracellular signal-regulated kinase1/2, protein kinase B, and glycogen synthase kinase 3b) known to be modulated by antidepressants and implicated in the control of proliferation/survival. Furthermore, as agomelatine possesses both melatonergic agonist and serotonergic (5-HT 2C ) antagonist properties, we determined whether melatonin and 5-HT 2C receptor antagonists similarly influence cell proliferation and survival. Only the 5-HT 2C receptor antagonists, SB243,213 or S32006, but not melatonin, mimicked the effects of agomelatine on cell proliferation in VH. The promoting effect of agomelatine on survival was not reproduced by the 5-HT 2C receptor antagonists or melatonin alone. However, it was blocked by a melatonin antagonist, S22153. These results show that agomelatine treatment facilitates all stages of neurogenesis and suggest that a joint effect of melatonin agonism and 5HT 2C antagonism may be involved in promotion by agomelatine of survival in the hippocampus.

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Acute brain injuries have been identified as a risk factor for developing Alzheimer's disease (AD). Because glutamate plays a pivotal role in these pathologies, we studied the influence of glutamate receptor activation on amyloid-␤ (A␤) production in primary cultures of cortical neurons. We found that sublethal NMDA receptor activation increased the production and secretion of A␤. This effect was preceded by an increased expression of neuronal Kunitz protease inhibitory domain (KPI) containing amyloid-␤ precursor protein (KPI-APP) followed by a shift from ␣-secretase to ␤-secretase-mediated APP processing. This shift is a result of the inhibition of the ␣-secretase candidate tumor necrosis factor-␣ converting enzyme (TACE) when associated with neuronal KPI-APPs. This KPI-APP/ TACE interaction was also present in AD brains. Thus, our findings reveal a cellular mechanism linking NMDA receptor activation to neuronal A␤ secretion. These results suggest that even mild deregulation of the glutamatergic neurotransmission may increase A␤ production and represent a causal risk factor for developing AD.

Accumulation of the amyloid-␤ peptide (A␤) in the brain is crucial for development of Alzheimer's disease. Expression of transforming growth factor-␤1 (TGF-␤1), an immunosuppressive cytokine, has been correlated in vivo with A␤ accumulation in transgenic mice and recently with A␤ clearance by activated microglia. Here, we demonstrate that TGF-␤1 drives the production of A␤40/42 by astrocytes leading to A␤ production in TGF-␤1 transgenic mice. First, TGF-␤1 induces the overexpression of the amyloid precursor protein (APP) in astrocytes but not in neurons, involving a highly conserved TGF-␤1-responsive element in the 5-untranslated region (؉54/؉74) of the APP promoter. Second, we demonstrated an increased release of soluble APP-␤ which led to TGF-␤1-induced A␤ generation in both murine and human astrocytes. These results demonstrate that TGF-␤1 potentiates A␤ production in human astrocytes and may enhance the formation of plaques burden in the brain of Alzheimer's disease patients.