Sustained activation of Akt by melatonin contributes to the protection against kainic acid‐induced neuronal death in hippocampus

Abstract

In the present study, the underlying protective mechanism of melatonin on kainic acid (KA)-induced excitotoxicity was examined in the hippocampus of mice. KA, administered intracerebroventricularly (i.c.v.), induced marked neuronal cell death with concurrent microglial activation and subsequent induction of inducible nitric oxide synthase (iNOS) in the hippocampus. Histopathological analysis demonstrated that melatonin (10 mg/kg), administered 1 hr prior to KA, attenuated KA-induced death of pyramidal neurons in the CA3 region. Melatonin obviously suppressed KA-induced microglial activation and consequent iNOS expression that were determined by increased immunoreactivities of microglial marker OX-6 and iNOS, respectively. Increased phosphorylation of Akt in pyramidal neurons was observed as early as 2 hr after administration of melatonin. Further, melatonin resulted in increased expression of astroglial glial cell line-derived neurotrophic factor (GDNF), which started to appear approximately 6 hr after administration of melatonin. The results of the present study demonstrate that melatonin exerts its neuroprotective action against KA-induced excitotoxicity both through the activation of neuronal Akt and via the direct action on hippocampal neurons and through the increased expression of astroglial GDNF, which subsequently activates neuronal PI3K/Akt pathway. Therefore, the present study suggests that melatonin, pineal secretory product, is potentially useful in the treatment of acute brain pathologies associated with excitotoxic neuronal damage such as epilepsy, stroke, and traumatic brain injury.

Driving GDNF expression: The green and the red traffic lights

“…VPA has been shown to activate the MAPK-ERK pathway in human neuroblastoma SH-SY5Y cells (Yuan et al, 2001) suggesting that this mechanism could be responsible for the VPA-induced GDNF up-regulation observed in other studies (Castro et al, 2005;Chen et al, 2006b). Melatonin, also known to increase the expression of GDNF (Tang et al, 1998;Armstrong and Niles, 2002;Chen et al, 2003;Lee et al, 2006), is able, via the MT1 receptor, to activate the MAPK-ERK pathway (Witt-Enderby et al, 2000).…”

Role of melatonin on calcium signaling and mitochondrial oxidativestress in epilepsy: focus on TRP channels

“…in association with the suprachiasmatic nucleus (Lee et al, 2006;Turgut et al, 2006). Intracellular ROS are scavenged by melatonin and its metabolites (Espino et al, 2012;Bejarano et al, 2014).…”

“…Intracellular ROS are scavenged by melatonin and its metabolites (Espino et al, 2012;Bejarano et al, 2014). Melatonin has been reported to modulate the L-type voltage-gated calcium channel (VGCC) channelopathies (Lee et al, 2006;Nazıroğlu, 2009;Choi et al, 2014), oxidative stress-activated TRPV1 and TRPM2 channels (Reuss et al, 2010;Nazıroğlu et al, 2012a), and glutamate receptors (Molina-Carballo et al, 2007). It is well known that the GABA neurotransmitter has an important role in the induction of epilepsy.…”

An Analog of a Dipeptide-Like Structure of FK506 Increases Glial Cell Line-Derived Neurotrophic Factor Expression through cAMP Response Element-Binding Protein Activated by Heat Shock Protein 90/Akt Signaling Pathway

“…Therefore, these findings, together with ours, further support a notion that chaperones like Hsp90 may participate in neuroprotection by conformational or chaperoning modulation of Akt rather than by acting on upstream effectors of the pathways. Additionally, Akt activation is required for increased expression of astroglial GDNF induced by melatonin (Lee et al, 2006).…”