Anti-Neuropathic Pain Property of Alantolactone in Paclitaxel-Induced Mouse Model

Abstract

Paclitaxel is the most frequently used anticancer drug for various carcinomas. It causes degeneration or dysfunction of peripheral nerve fibers in patients, leading to discontinuation of therapy. The current study was intended to develop a paclitaxel induced model and identification of molecular mechanism involved in the progression of neuropathy, and of action alantolactone in the attenuation of peripheral neuropathy. Alantolactone has diverse pharmacological actions. We explored the anti-nociceptive potential of alantolactone in the paclitaxel-induced neuropathic pain model. Data of behavioral testing manifested that alantolactone efficaciously inhibited hyperalgesia and allodynia. Moreover, alantolactone markedly increased muscle strength and motor coordination caused by paclitaxel administration in mice. Alantolactone downregulated the expression of nociceptors TRPV1/P2Y in the sciatic nerve and spinal cord. In the spinal cord, it remarkably decreased the expression of TLR4 and its downstream signaling. The impact of alantolactone on the NFκB signaling pathway manifested that it has the ability to inhibit the degradation of IκB-α and transfer of NFκB subunits inside of the nucleus. In the sciatic nerve and spinal cord, alantolactone decreased oxidative stress moreover reduced the production of inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β). Besides this, alantolactone inhibited “Mitogen-activated Protein kinases (MAPKs), including Jun N-terminal kinase (pJNK), extracellular signal-regulated kinase (pERK), p38, and activator protein-1 (AP1)” in paclitaxel-induced neuropathic pain (PINP) model. Meanwhile, it also augmented Bcl2 expression and reduced caspases-3. Pharmacokinetics and toxicokinetic study revealed that ALN showed good BBB permeability and GIT absorption with less toxicity. ALN docked well with target proteins complex. Data analysis concluded that alantolactone is the potential candidate for the treatment of PINP via suppressing inflammation and decreasing expression of nociceptors in the sciatic nerve and spinal cord. Keywords: Neuropathic pain, neurodegenration, neuroinflammation, oxidative stress, neuroprotection