Basically what I could surmise(see below) is that caspase-3 can be activated in a number of situations as a causation of "extrinsic apoptotic pathways"...one of which can result in cerebral hypoxia -perhaps the seizure component of Wellbutrin...?
It seems reasonable to me that proper supplementation with antioxidants, proper hydration and vasodilators can help reduce possible cytotoxicity...
The endoplasmic reticulum stress response in immunity and autoimmunity
ER linkMolecular mechanisms of cerebral ischemia-induced neuronal death
Link to MechanismsWiki link to Info on Cerebral HypoxiaSelective, Reversible Caspase-3 Inhibitor Is Neuroprotective and Reveals Distinct Pathways of Cell Death after Neonatal Hypoxic-ischemic Brain Injury*
Hypoxic-ischemic (H-I)1encephalopathy in the prenatal and perinatal period is a major cause of morbidity and mortality and often results in cognitive impairment, seizures, and motor impairment leading to cerebral palsy (1, 2). Many studies of neonatal H-I brain injury have utilized the well characterized Levine model in which unilateral carotid ligation is followed by exposure to hypoxia in postnatal day (P) 7 rats (3-5). This model of H-I results in a reproducible pattern of hemispheric injury ipsilateral, but not contralateral, to the carotid ligation (5-7). There are prominent features of both apoptosis and necrosis when this model is performed in neonatal rats and mice (1, 8-11). Inhibition of caspases utilizing a pan-caspase inhibitor partially protects against brain injury after neonatal H-I injury in this model (12), and similar inhibitors have been shown to partially protect against ischemic injury in adult models (13-16). Previously utilized peptide-based caspase inhibitors (e.g. Boc-D-fmk, z-VAD-fmk, z-DEVD-fmk) required relatively large doses in vivo for their protective effects, and at high concentrations, their effects are more likely to be less selective. Thus, although these studies suggest a role for caspases, the specific caspases and other proteases, which contribute to brain injury after neonatal H-I, have not been clarified.
Info on Caspases:
Caspases are a family of cysteine aspartyl-specific proteases. They are mammalian homologues of CED-3, which is required for programmed cell death in the nematode Caenorhabditis elegans (17). To date, 13 mammalian caspases have been identified that share similarities in amino acid sequence, structure, and biochemical properties (18-20). They are normally expressed as proenzymes (30–50 kDa) comprising an N-terminal prodomain, a large subunit (∼20 kDa), and a small subunit (∼10 kDa). Activation of caspases requires proteolytic processing between domains and formation of a heterodimer containing the large and small subunits. Each activated caspase recognizes distinct tetrapeptide motifs leading to the diversity of substrate specificity and intracellular function (21). The apoptotic initiators (caspase-2, -8, -9, and -10) containing large N-terminal prodomains generally act upstream of small prodomain effector caspases (caspase-3, -6, and -7).
Caspase-3, among effector caspases, has been implicated in neuronal apoptosis during normal brain development and in delayed neuronal cell death after brain injury in the developing and adult brain (9, 22-25). Once activated, caspase-3 is directly responsible for proteolytic cleavages of a variety of fundamental proteins including cytoskeletal proteins, kinases, and DNA-repair enzymes (26-29). Caspase-3 activation can irreversibly commit cells to undergo morphological features of apoptosis including nuclear condensation and DNA fragmentation. At least two different initiator caspases, caspase 8 and 9, can be responsible for activation of caspase-3 through distinct cellular signaling pathways (30-39). Because caspase-3 is known to be a major contributor to the apoptotic machinery in many cell types, development of selective and potent caspase-3 inhibitors has emerged as a therapeutic target.
We have utilized a new small, reversible inhibitor of caspase-3, M826, to determine the role of caspase-3 after neonatal H-I as well as to develop a compound that may have therapeutic potential. M826 demonstrated high selectivity and potency toward caspase-3 in recombinant enzyme-based as well as whole cell-based assays. It also blocked almost all caspase-3 activation and its substrate cleavage after neonatal H-I. Despite this, early excitotoxic/necrotic cell death associated with calpain activation and cleavage but not activation of caspase-2 was still present in caspase-3 inhibitor-treated animals. Our results suggest that caspase-3 contributes to delayed cell death and that early events associated with calpain activation may be involved in the rapidly occurring excitotoxic/necrotic component of cell death after neonatal H-I.
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