Autophagy and autophagy signaling in Epilepsy: possible role of autophagy activator

Abstract

Autophagy is an explicit cellular process to deliver dissimilar cytoplasmic misfolded proteins, lipids and damaged organelles to the lysosomes for degradation and elimination. The mechanistic target of rapamycin (mTOR) is the main negative regulator of autophagy. The mTOR pathway is involved in regulating neurogenesis, synaptic plasticity, neuronal development and excitability. Exaggerated mTOR activity is associated with the development of temporal lobe epilepsy, genetic and acquired epilepsy, and experimental epilepsy. In particular, mTOR complex 1 (mTORC1) is mainly involved in epileptogenesis. The investigation of autophagy's involvement in epilepsy has recently been conducted, focusing on the critical role of rapamycin, an autophagy inducer, in reducing the severity of induced seizures in animal model studies. The induction of autophagy could be an innovative therapeutic strategy in managing epilepsy. Despite the protective role of autophagy against epileptogenesis and epilepsy, its role in status epilepticus (SE) is perplexing and might be beneficial or detrimental. Therefore, the present review aims to revise the possible role of autophagy in epilepsy.

Keywords: Autophagy; Autophagy inducers; Epilepsy; Neurodegeneration; Seizure.

Fig. 1

Pathophysiology of epilepsy. Decreasing inhibitory gamma-aminobutyric acid (GABA) and increasing excitatory glutamate persuade the progress and progression of epileptogenesis

Fig. 2

Pathway of autophagy. ATG1 complex, Beclin 1 and vacuolar sorting protein 34 (Vps34) triggered the formation of nascent autophagosomes from phagophores then with the assistance of LC3 form immature autophagosomes which are converted to mature autophagosomes. With the assistance of autophagic flux, mature autophagosomes together with lysosomes form autolysosomes

Fig. 3

Regulation of autophagy: Growth factors like insulin-like growth factor (IGF) through activation of IGF receptors (IGFRs) enhence the activity of tyrosine kinase and Aκt leading to activation of the mTOR pathway and inhibition of autophagy

Fig. 4

Autophagy and epilepsy. Sirtuin-1 (SIRT1) activates FOXO3, and autophagy, inhibits P53 and promotes peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PC-1α) which reduces mitochondrial dysfunction. Phospholipase D inhibits autophagy through activation of mTOR, inhibition of AMPK and inhibition of the interaction between Beclin-1 and vacuolar sorting protein 34 (Vps34). P53 and IP3 inhibit autophagy through the activation of the mTOR pathway and endoplasmic reticulum (ER) IP3 receptors, respectively. Additionally, autophagy is activated by Atg7 and glycogen synthase kinase 3 (GSK3). GSK3 inhibits the mTOR pathway which is implicated in epileptogenesis

Fig. 5

Mechanistic effects of autophagy inducers in epilepsy: Rapamycin inhibits mTORC1 and attenuates T cell migration and development of neuroinflammation which trigger epilepsy. Additionally, Rapamycin activates the FK506-binding protein that regulates gamma-aminobutyric acid (GABA) ergic neurons and expression of glutamate receptors in astrocytes thereby reducing seizures. Metformin has anti-seizure activity by activating 5’ AMP-activated protein kinase (AMPK) signaling and inhibiting mTOR pathways which are dysregulated in epilepsy. AMPK improves the expression of glucose transporter 1 (GLUT1) and peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) which improves mitochondrial biogenesis, and upregulates Sirtuin1 (SIRT1), Forkhead box O3 (FOXO3), progranulin and GABA which induce neuroprotection. Ibuprofen has a neuroprotective and anti-seizure effect by inhibiting cyclooxygenase (COX) and heat shock protein 90 (Hsp90) for the induction of autophagy. Lithium inhibits the expression and activity of glycogen synthase kinase-3 beta (GSK3β) and inositol trisphosphate (IP3) which are the negative regulators of autophagy