Mohammad Rafi Khezri - Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran.
Naime Majidi Zolbanin - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
Morteza Ghasemnejad-berenji - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
Reza Jafari - Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran

Neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, are caused by dysfunction and loss of neurons in the central nervous system. Different triggering factors are involved in the loss of neurons (e.g., stress oxidative, inflammatory responses, and excitotoxicity) followed by gene mutations and aggregated proteins' formation. Additionally, the activity of non-neuronal cells (astrocytes and microglia) is involved in increasing or decreasing the progression of the so-called diseases. A method of preventing the progression of neurodegenerative diseases is to affect the PI۳K/AKT signaling pathway activity, which is associated with various aspects of cell survival and protein synthesis. Since various drugs with low side effects are known to affect the PI۳K/AKT signaling pathway, the present review aims to introduce this pathway as a candidate for therapeutic interventions in neurodegenerative diseases. In this review, the keywords of neurodegenerative diseases, PI۳K/AKT pathway, inflammation, excitotoxicity, and oxidative stress in the title and abstract of articles in the international databases, PUBMED, Science Direct, and Cochran library were searched, that through existing research ۴۱۱ related articles were obtained, with study of the articles abstract. ۱۸۱ articles were chosen for comprehensive review. The PI۳K/AKT signaling pathway plays a crucial role in regulation of aggregated proteins expression in neurodegenerative diseases. Activation of this pathway contributes to inhibit oxidative stress through activation of several transcription factors such as Nrf۲ leading to increase the expression of antioxidant enzymes. Additionally, the PI۳K/AKT signaling pathway suppresses the apoptosis of neurons via balancing the expression of pro-apoptotic and anti-apoptotic factors. The PI۳K/AKT signaling pathway regulates the activity of microglia cells and astrocytes. In microglia, the PI۳K/AKT signaling pathway is closely related to the expression of inflammatory cytokines such as IL-۶ and TNF-α, which involved in the progression of neurodegenerative diseases. Also, the PI۳K/AKT signaling pathway induces the expression of tight junction proteins leading to suppress blood-brain barrier breakdown in neurodegenerative diseases. Regarding the astrocytes, this pathway modulates the effect of these cells on glutamate excitotoxicity and glucose transport through increasing the expression of glutamate transporters (e.g., EAAT۱) and glucose transporters (e.g., GLUT۱), respectively. Based on the available evidence, the PI۳K/AKT signaling pathway is an appropriate target for therapeutic interventions in neurodegenerative diseases.

neurodegenerative diseases, PI۳K/AKT pathway, inflammation, excitotoxicity, stress oxidative