The mechanism for the neuroprotective effect of melatonin against methamphetamine‐induced autophagy

Abstract

Methamphetamine (METH) is a common drug of abuse that induces toxicity in the central nervous system and is connected to neurological disorders such as Parkinson's disease. METH neurotoxicity is induced by reactive oxygen species (ROS) production and apoptosis. Moreover, autophagy is an alternative to cell death and a means for eliminating dysfunctional organelles. In other cases, autophagy can end up in cell death. Nonetheless, it is not clear whether autophagy is also correlated with apoptotic signaling in drug-induced neurotoxicity. Therefore, we hypothesized that METH-generated toxicity associated with initiating the apoptotic signaling cascade can also increase the autophagic phenotype in neuronal cells. Using the SK-N-SH dopaminergic cell line as our model system, we found that METH-induced autophagy by inhibiting dissociation of Bcl-2/Beclin 1 complex and its upstream pathway that thereby led to cell death. We uncovered a novel function for the anti-apoptotic protein Bcl-2, as it played a role in negatively regulating autophagy by blocking an essential protein in the signaling pathway, Beclin 1. Furthermore, Bcl-2 was activated by c-Jun N-terminal kinase 1 (JNK 1), which is upstream of Bcl-2 phosphorylation, to induce Bcl-2/Beclin 1 dissociation. Furthermore, we demonstrated a novel role for melatonin in protecting cells from autophagic cell death triggered by the Bcl-2/Beclin 1 pathway by inhibiting the activation of the JNK 1, Bcl-2 upstream pathway. This study provides information regarding the link between apoptosis and autophagy signaling, which could lead to the development of therapeutic strategies that exploit the neurotoxicity of drugs of abuse.

Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats

“…It has been shown that oestradiol reduced mRNA levels of the pro-apoptotic Bad in PC12 cells transfected with ERα (Gollapudi and Oblinger 1999). Nopparat et al (2010) have demonstrated, in the SK-N-SH dopaminergic cell line, a novel role of melatonin in protecting cells from autophagic cell death triggered by the Bcl-2/Beclin 1 pathway, by inhibiting the activation of the JNK1 (cJun amino-terminal kinase), Bcl-2 upstream pathway. Melatonin increased Bcl-2 and augmented expression of XIAP in ethanol-treated HN2-5 (mouse hippocampal neuron-derived) cells (Shetha et al 2009).…”

Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

“…42 It also has protective effects on methamphetamine-induced autophagic cell death in vitro. 48 We tested whether exogenous adding of melatonin could prevent MPTP-induced autophagy and cell death. As shown in Figure 3A and B, melatonin could restore the elevated CDK5 level induced by MPTP in C6 cells.…”

Effects of Melatonin on Nervous System Aging: Neurogenesis and Neurodegeneration

“…A deficiency in the autophagy-related protein beclin1 modulates amyloid precursor protein accumulation and promotes neurodegeneration (207). Melatonin protects neurons against the Bcl2/Beclin1 autophagic cell death pathway by the activation of the JNK1/Bcl2 cascade (208) and modulates mTOR activity and 4E-BP1 phosphorylation (209).…”