**7. Role of HIF 1a in causing hypoxia in the brain**

A transcription factor that binds to specific nuclear cofactors and transactivates several genes, causing a range of adaptive responses in response to low oxygen levels

#### *Impact of Hypoxia on Astrocyte Induced Pathogenesis DOI: http://dx.doi.org/10.5772/intechopen.106263*

in the body, is called Hypoxia Inducible Factor *HIF* [41]. *HIF-1* alpha and beta subunits form an active heterodimer under hypoxic settings, driving the transcription of approximately 60 genes involved in cell survival, adaptability, anaerobic metabolism, cytokine generation, vascularization, immunological response, and tissue homeostasis [42]. The two isoforms of *HIFα*, *HIF1α,* regulate erythropoietin (EPO), whereas *HIF2α* regulates the heme-regulating gene (hemopoietin genes). Increased *HIF* signalling in the body can contribute to inflammation and tumour progression. *HIF2α* activation has been observed because it plays a fundamental role in inflammation. HIF-1α has neuroprotective properties, but it can potentially be neurotoxic. *HIF-1* is involved in forming the early brain and the proliferation of neural precursor cells. *HIF-1* is recognized as critical in hypoxic–ischemic brain damage under pathological conditions [43]. During hypoxia, *HIF-1* participates in the apoptotic process to increase the stability of the tumour suppressor protein p53, which has neurotoxic consequences.

The brain is the most vulnerable organ to hypoxia, resulting in coma, convulsions, cognitive impairment, other neurological impairments, and brain death if left untreated [44]. Cardiac arrest, asphyxia, or systemic metabolic abnormalities affecting the blood's oxygen content, systemic hypoxia, severe anaemia, and systemic hypotension can lead to hypoxic brain damage [45]. Hypoxia-induced autophagy is linked to the HIF-1 signalling pathway. According to studies, hypoxic preconditioning protection is lost in HIF-1α knockout mice exposed to neonatal hypoxia/ischemia [46]. HIF1α hydroxylation is prevented by blockage of prolyl- and asparaginyl-hydroxylases in hypoxic environments. Prolyl-hydroxylase inhibitors reduce HIF1α breakdown, resulting in fast *HIF1α* protein build-up [47]. Phosphorylation of the *HIF1α* protein causes it to dimerize with *HIF1α*. The *HIF1α*/*HIF1β* dimer interacts with p300/CBP, causing hypoxia response elements in *HIF* target genes to be activated [48].

PI3K (Phosphatidylinositol 3-kinase) and Akt (protein kinase B) signalling pathway is related to hypoxia-ischemia injury as it increases the phosphorylation of downstream molecules such as apoptosis-related family members, transcription factors, mammalian target of rapamycin (mTOR), and glycogen synthase kinase-3. Phosphatase and tensin homologue (PTEN) is a lipid phosphatase that inhibits the PI3K/Akt pathway by hydrolysing PIP-3 to PIP-2 and preventing downstream p-Akt. PI3K and its downstream effector. Akt is a member of a well-studied family of signal transduction enzymes that regulate cellular activation, inflammation, and apoptosis [49].
