Table 1.

Different cell death Pathways associated with spinal cord injury and their therapeutic interventions

Classification	Mode of cell death	Relation to pathogenesis in SCI	Treatment method targeting pathways	References
Programmed apoptotic cell death	Extrinsic apoptosis Intrinsic apoptosis	1. Death of astrocytes, neurons, mi- croglia, and oligodendroglia	1. XIST KO to reduce neuronal death.	[36,38,39,43]
			2. Targeting CARD6 to block Caspase-3
		2. Promote Wallerian degeneration	3. Minocycline to block CD95 [Fas] ligand
			4. Glycol to block sphingolipid-induced iNOS
			5. Metformin to increase β-catenin and BDNF expression
	Anoikis	1. Impairment of ECM remodeling	1. Use of MSCs	[46,47]
		2. Promote myelin degeneration	2. Use of BDNFs
Programmed nonapoptotic cell death	Autophagy	1. Stabilization of microtubules by degradation of SCG10	1. Metformin to increase autophagy in SCI cells	[57,58,65]
		2. increase in axon development	2. SCG10 to promote microtubule stabiliza- tion and axon recovery
		3. Protection of neurons from ER stress	3. ABT888 to suppress autophagy
	Paraptosis	1. Increase in p44 expression in the CNS to promote neuronal death	Not discovered yet	[73]
	Mitoptosis	1. Cell death in penumbra and lesion after SCI by elevation of Bax: Bcl-2 ratio	Being researched	[85]
	Parthanatos	1. Kainite excitotoxicity	1. 6-5[H]-phenanthridine to prevent AIF translocation and overactivation of PARP-1	[96,97]
		2. Oxidative stress	2. PJ34 to reduce kainite excitotoxicity
	Ferroptosis	1. Excitotoxicity-induced cell death	1. Deferoxamine to lower Fe2+ levels	[105]
			2. Proanthocyanidins to suppress ferroptosis and promote functional recovery
	Netosis	1. Promoting Secondary injury by HOCl formation.	Being researched	[123,131]
		2. Producing NETs to worsen the injury
		3. Cell swelling by HMGB1 induced AQP4 activation
	Pyroptosis	1. Neuronal death by GSDMD cleavage by caspase 1	Being researched	[110]
	Necroptosis	1. TNFR-induced cell death	1. PSMB4 by regulating RIP3w and MLKLpathways	[83]
			2. NEC-1 by recruiting RIP1/3–MLKL
Nonprogrammed nonapoptotic cell death	Nonprogrammed necrosis	1. Neurological impairment	Being researched	[162,164]
		2. spinal cord tissue loss
		3. Cystic cavitation of the spinal cord
		4. NMDA excitotoxicity

SCI, spinal cord injury; XIST, X-inactive specific transcript; CARD6, caspase recruitment domain-containing protein 6; CD95, cluster of differentiation 95; iNOS, inducible nitric oxide synthase; BDNF, brain-derived neurotrophic factor; ECM, extra cellular matrix; MSCs, mesenchymal stem cells; SCG10, stathmin-2; ER, endoplasmic reticulum; SCI, spinal cord injury; CNS, central nervous system; Bax, Bcl-2-like protein; Bcl-2, B-cell lymphoma; PARP1, poly[ADP-ribose]-polymerase 1; PJ34, PARP inhibitor; HOCl, hypochlorous acid; NETs, neutrophil extracellular traps; HMGB1, high mobility group box 1; AQP4, aquaporin 4; GSDMD, gasdermin D; TNFR, tumor necrosis factor receptors; PSMB4, 20S proteasome subunit beta-7; RIP3, receptor-interacting serine/threonine kinase 3; MLKL, mixed lineage kinase domain-like pseudokinase; Nec1, necrostatin 1; NMDA, N-methyl-D-aspartate.