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.

Hypothyroidism (HPT) HPT could be a risk factor for the development and progression of Alzheimer’s disease (AD). In addition, progressive neurodegeneration in AD may affect the metabolism of thyroid hormones (THs) in the brain causing local brain HPT. Hence, the present review aimed to clarify the potential association between HPT and AD. HPT promotes the progression of AD by inducing the production of amyloid beta (Aβ) and tau protein phosphorylation with the development of synaptic plasticity and memory dysfunction. Besides, the metabolism of THs is dysregulated in AD due to the accumulation of Aβ and tau protein phosphorylation leading to local brain HPT. Additionally, HPT can affect AD neuropathology through various mechanistic pathways including dysregulation of transthyretin, oxidative stress, ER stress, autophagy dysfunction mitochondrial dysfunction, and inhibition of brain-derived neurotrophic factor. Taken together there is a potential link between HPT and AD, as HPT adversely impacts AD neuropathology and the reverse is also true. Graphical Abstract

Parkinson’s disease (PD) is a neurodegenerative disease due to the degeneration of dopaminergic neurons (DNs) in the substantia nigra (SN). The liver X receptor (LXR) is involved in different neurodegenerative diseases. Therefore, the objective of the present review was to clarify the possible role of LXR in PD neuropathology. LXRs are the most common nuclear receptors of transcription factors that regulate cholesterol metabolism and have pleiotropic effects, including anti-inflammatory effects and reducing intracellular cholesterol accumulation. LXRs are highly expressed in the adult brain and act as endogenous sensors for intracellular cholesterol. LXRs have neuroprotective effects against the development of neuroinflammation in different neurodegenerative diseases by inhibiting the expression of pro-inflammatory cytokines. LXRs play an essential role in mitigating PD neuropathology by reducing the expression of inflammatory signaling pathways, neuroinflammation, oxidative stress, mitochondrial dysfunction, and enhancement of BDNF signaling.In conclusion, LXRs, through regulating brain cholesterol homeostasis, may be effectual in PD. Also, inhibition of node-like receptor pyrin 3 (NLRP3) inflammasome and nuclear factor kappa B (NF-κB) by LXRs could effectively prevent neuroinflammation in PD. Taken together, LXRs play a crucial role in PD neuropathology by inhibiting neuroinflammation and associated degeneration of DNs.

Alzheimer’s disease (AD) is the most common type of dementia associated with amyloid beta (Aβ) deposition. Dysfunction of the neuronal clearance pathway promotes the accumulation of Aβ. The plasminogen-activating system (PAS) is controlled by various enzymes like tissue plasminogen activators (tPA). Neuronal tPA enhances the conversion of plasminogen to plasmin, which cleaves Aβ; this function is controlled by many inhibitors of PAS, including a plasminogen-activating inhibitor (PAI-1) and neuroserpin. Therefore, the objective of the present narrative review was to explore the potential role of tPA/neuroserpin in the pathogenesis of AD. PAI-1 activity is increased in AD, which is involved in accumulating Aβ. Progressive increase of Aβ level during AD neuropathology is correlated with the over-production of PAI-1 with subsequent reduction of plasmin and tPA activities. Reducing plasmin and tPA activities promote Aβ by reducing Aβ clearance. Neuroserpin plays a critical role in the pathogenesis of AD as it regulates the expression and accumulation of Aβ. Higher expression of neuroserpin inhibits the neuroprotective tPA and the generation of plasmin with subsequent reduction in the clearance of Aβ. These observations raise conflicting evidence on whether neuroserpin is neuroprotective or involved in AD progression. Thus, neuroserpin over-expression with subsequent reduction of tPA may propagate AD neuropathology. Graphical abstract