**5. Astrocyte up-regulation**

Astrocyte is the essential part of the blood–brain barrier (BBB) that can be damaged by traumatic brain injury (TRI) or ischemia. Astrocytes provide the morphological and physiological link between neural networks and cerebral circulation. Astrocytes have the power to adjust blood flow to the brain to keep the brain parenchyma's PCO2 and PO2 steady [21]. The formation of ATP in the brainstem through local astrocytes aids respiration and counters hypoxia-induced respiratory network depression. Hypoxia-induced alterations in brain inflammation, neuroprotection, and blood–brain barrier permeability against ischemic injury appear to be mediated by astrocytes. Astrocytes play a critical function in neuronal function in everyday situations and pathological conditions when the supply of oxygen to the brain is disrupted [22].

The telomerase reverse transcriptase (TERT) gene is linked to cell injury and stress resistance. After hypoxia-ischemia, protein and TERT mRNA were increased in neurons after a few days but moved to astrocytes [23]. TERT overexpression decreased astrocyte multiplication by upregulating the cell-cycle regulatory protein p15. While neurons were cultured with precondition medium from astrocytes with TERT inhibition contrasted to neurotrophin-3 expression, TERT overexpression in astrocytes decreased, resulting in higher death [24]. In TERT-overexpressing brains with hypoxia-ischemia, neuronal damage and Ki67-positive astrocytes were also suppressed [25].

Matrix metalloproteinase (MMP)-9 is an endo-peptidase that plays a crucial role in Blood–Brain Barrier proteolysis post-trauma and leads to cell death with persistent convulsions [26]. Activation of mitogen-activated protein kinases (MAPKs) in astrocytes can be caused by thrombin, oxidative stress, tissue plasminogen activator, or tumour necrosis factor- α and includes stimulation of MMP-9. In astrocytes, albumin causes a rise in MMP-9 synthesis, which requires ROS formation and motivation of the MAPK pathway [27]. These results add albumin to signalling molecules that activate MMP-9 in astrocytes alongside thrombin. These findings connect albumin to MMP-9-mediated cellular mechanisms such as intracerebral haemorrhage, neuronal damage, dendritic remodelling, and epileptogenesis [28].

Stroke and Traumatic Brain Injury (TBI) are frequently linked with hypoxia, which causes glial initiation. Glial cells, particularly astrocytes, play an essential part in stress prevention and the homeostasis of the CNS by offering structural and metabolic stability [29]. Hypoxia can cause astrocyte homeostasis to be disrupted, resulting in cell enlargement. Wnt pathway suppression was the most substantially disrupted signalling pathway in the mechanism of hypothermia-induced responses in human astrocytes after oxidative stress activation and hypoxia [30]. Global suppression of Wnt signalling can be troublesome because of its essential role in controlling critical mechanisms associated with the functional regulation of immune and stem cells and its effect on post-mitotic neuronal and glial cells [31].
