Inhibition of Caspase 3 and Caspase 9 Mediated Apoptosis: A Multimodal Therapeutic Target in Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is one of the significant causes of death and morbidity, and it is hence a focus of translational research. Apoptosis plays an essential part in the pathophysiology of TBI, and its inhibition may help overcome TBI’s negative consequences and improve functional recovery. Whereas physiological neuronal death is necessary for appropriate embryologic development and adult cell turnover, it can also drive neurodegeneration. Caspases are principal mediators of cell death due to apoptosis and are critical to the required cleavage of intracellular proteins of cells committed to die. Caspase-3 is the major executioner Caspase of apoptosis and is regulated by a range of cellular components during physiological and pathological conditions. Activation of Caspase-3 causes proteolyzation of DNA repair proteins, cytoskeletal proteins, and the inhibitor of Caspase-activated DNase (ICAD) during programmed cell death, resulting in morphological alterations and DNA damage that define apoptosis. Caspase-9 is an additional crucial part of the intrinsic pathway, activated in response to several stimuli. Caspases can be altered post-translationally or by modulatory elements interacting with the zymogenic or active form of a Caspase, preventing their activation and activity. The necessity of Caspase-9 and -3 in diverse apoptotic situations suggests that mammalian cells have at least four distinct apoptotic pathways. Continued investigation of these processes is anticipated to disclose new Caspase regulatory mechanisms with consequences far beyond apoptotic cell death control. The present review discusses various Caspase-dependent apoptotic pathways and the treatment strategies to inhibit the Caspases potentially.

YTHDF1 Attenuates TBI-Induced Brain-Gut Axis Dysfunction in Mice

“…Our results showed that the deletion of YTHDF1 could mitigate structural lesions in both brain and gut tissues post-TBI. At the protein level, apoptosis is potentiated [ 32 , 33 , 34 ], marked by upregulated caspase3 [ 35 , 36 , 37 , 38 ], Cleaved caspase-3 [ 39 ] and BAX, as well as downregulated BCL2 [ 40 , 41 ]. Meanwhile, inflammation is enhanced [ 42 ], such as increased CD68 cells [ 42 , 43 , 44 ] and decreased Foxp3-mediated regulatory T cells (Tregs) [ 45 , 46 , 47 ].…”

Proteomic-Based Approach Reveals the Involvement of Apolipoprotein A-I in Related Phenotypes of Autism Spectrum Disorder in the BTBR Mouse Model

“…In the hippocampal tissues of BTBR mice, we found alterations in the pro-apoptotic protein caspase-3, which has been identified as a key mediator of physiological neuronal apoptosis [ 47 ]. The cell lymphoma-2 (Bcl-2) family proteins participate in cell apoptosis and play an important role in regulating neuronal apoptosis and axonal degeneration [ 48 ].…”

Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review

“…Apoptosis is mediated by a caspase (cysteine aspartyl-specific protease) that cleaves target proteins [174]. Caspase protease activity cleaves hundreds of diverse proteins and is essential for apoptosis [175].…”