Advances in the mTOR signaling pathway and its inhibitor rapamycin in epilepsy

Abstract

Introduction: Epilepsy is one of the most common and serious brain syndromes and has adverse consequences on a patient's neurobiological, cognitive, psychological, and social wellbeing, thereby threatening their quality of life. Some patients with epilepsy experience poor treatment effects due to the unclear pathophysiological mechanisms of the syndrome. Dysregulation of the mammalian target of the rapamycin (mTOR) pathway is thought to play an important role in the onset and progression of some epilepsies.Methods: This review summarizes the role of the mTOR signaling pathway in the pathogenesis of epilepsy and the prospects for the use of mTOR inhibitors. Results:The mTOR pathway functions as a vital mediator in epilepsy development through diverse mechanisms, indicating that the it has great potential as an effective target for epilepsy therapy. The excessive activation of mTOR signaling pathway leads to structural changes in neurons, inhibits autophagy, exacerbates neuron damage, affects mossy fiber sprouting, enhances neuronal excitability, increases neuroinflammation, and is closely associated with tau upregulation in epilepsy. A growing number of studies have demonstrated that mTOR inhibitors exhibit significant antiepileptic effects in both clinical applications and animal models. Specifically, rapamycin, a specific inhibitor of TOR, reduces the intensity and frequency of seizures. Clinical studies in patients with tuberous sclerosis complex have shown that rapamycin has the function of reducing seizures and improving this disease. Everolimus, a chemically modified derivative of rapamycin, has been approved as an added treatment to other antiepileptic medicines. Further explorations are needed to evaluate the therapeutic efficacy andThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cognitive Impairment in Multiple Sclerosis

“…In general, autophagy consists of the recycling of cytoplasmic organelles and proteins that can lead to the remodeling and formation of new tissue structures [34,44,61,100,169,202,[242][243][244][245]. Although the process of macroautophagy is usually described, other subsets of autophagy exist that include microautophagy and chaperone-mediated autophagy.…”

“…MS and demyelinating disease can be significantly impacted by the mechanistic target of rapamycin (mTOR) pathways (Figure 1). mTOR is a 289-kDa serine/threonine protein kinase that is encoded by a single gene, FRAP1 [13,46,71,73,98,124,243,244,393] (Table 1). mTOR is also known as the mammalian target of rapamycin and the FK506-binding protein 12-rapamycin complex-associated protein 1 [22,98,229].…”

“…Autophagy pathways are also critical for impacting neurodegeneration and usually involve the blockade of mTOR activity for neuroprotective pathways [17,22,44,70,100,105,169,[242][243][244]259,293]. The induction of autophagy, which may require an mTOR blockade, can protect neuronal and non-neuronal cells [10,24,73,89,106,172,224,442].…”

“…In regard to MS, mTOR can importantly impact inflammatory pathways that lead to neurodegeneration [3,73,85,211,244,285,461,462]. In clinical studies, mTOR pathway molecules may play an important role in determining the onset and progression of MS in patients [135].…”

Cornerstone Cellular Pathways for Metabolic Disorders and Diabetes Mellitus: Non-Coding RNAs, Wnt Signaling, and AMPK

“…Autophagy is another programmed cell death pathway that is involved in the sequestration of cytoplasmic proteins and organelles for recycling and tissue remodeling [59,246,274,275,[354][355][356][357][358]. Most descriptions of autophagy involve macroautophagy, rather than microautophagy or chaperone-mediated autophagy [59,359], which can form autophagosomes for combining into lysosomes.…”