Table 1.

Neuroprotective and antinociceptive strategies for targeting CIPN

Mechanism		Drug/Target examples	Effects	References
Neuroprotective strategies	• Mitochondrial dysfunction and disruption of calcium homeostasis	• Inhibitor of N-type and T-type voltage-gated calcium channels	• Reversal of paclitaxel-induced neuropathy	[44–47]
	• Oxidative stress	• A3 adenosine receptor agonist	• Decreased NADPH oxidase and mechanical allodynia in a paclitaxel-induced CIPN rat model	[49]
		• PPAR nuclear hormone receptor family	• Increased antioxidant activity of enzymes, superoxide dismutase, and catalase	[50–53]
		• APE1/Ref-1 base excision repair	• Increased anti-tumor activity and neuroprotection against platinum-induced CIPN	[54]
	• Activation of immune system and cytokines	• Inhibitors of pro-inflammatory cytokines TNF-⍺, IL-1, IL-6, IL-8	• Reversal of paclitaxel-induced neuropathy and microtubule destabilization	[57–62]
	• Increased activity of signaling pathways	• AMPK activators, inhibitor of mTOR and MAPK signaling pathways	• Prevention of paclitaxel and cisplatin-induced mechanical hypersensitivity	[63, 64]
		• Angiotensin II (type 1) antagonist	• Reversal of vincristine-induced tactile allodynia, decreased paclitaxel-induced neuropathy	[68, 69]
	• Axonal degeneration	• Inhibition of HDAC6 and nicotinamide mononucleotide (NMN)	• Decreased CIPN and promotion of microtubule stabilization and mitochondrial transport	[72, 73]
		• Inhibition of SARM1	• Prevent CIPN by targeting Wallerian degeneration	[39, 40]
Antinociceptive strategies	• Changes in activity of neurotransmitters and transporters	• Serotonergic agents: duloxetine and topical (10%) amitriptyline (SNRIs)	• Decreased CIPN	[24, 81]
		• Inhibition of glutamate release	• Restored nerve conduction and bortezomib-induced mechanical hyperalgesia. Decreased vincristine- and oxaliplatin-induced CIPN	[86–95]
	• Abnormal discharge of pain fibers (A$\delta$ and C fibers) and increased nociceptive signaling	• Cannabidiol analog	• Reduced paclitaxel-induced mechanical allodynia	[85, 86]
		• FAAH and MAGL, hydrolytic enzymes of endocannabinoids	• Decreased spontaneous discharge of pain fibers and attenuation of paclitaxel-induced CIPN	[106–109]
		• Non-psychotropic CB2 cannabinoid receptor agonist	Analgesic for paclitaxel-induced allodynia	[110, 111]
	• Neuronal hyperexcitability through TRP superfamily, voltage-gated sodium channels, and nicotinic acetylcholine receptors (nAChRs)	• Modulators of TRPA1, TRPM8, TRPV1, TRPV4	• Reversal of taxol, bortezomib, oxaliplatin-induced CIPN	[114–118]
		• Blockade of voltage-gated sodium channels (NaV 1.7, NaV 1.8, NaV 1.9)	• Reversal of CIPN through pharmacological blockade	[125–128]
		• Selective α9α10 nAChR subtype antagonist and α7 nAChR subtype agonist	• Prevention of oxaliplatin-induced CIPN	[119, 120]