Abstract
Paclitaxel-induced peripheral neuropathy (PIPN) is often associated with neuropathic pain and neuroinflammation in the central and peripheral nervous system. Antihypertensive drug losartan, an angiotensin II receptor type 1 (AT1R) blocker, was shown to have anti-inflammatory and neuroprotective effects in disease models, predominantly via activation of peroxisome proliferator-activated receptor gamma (PPARγ). Here, the effect of systemic losartan treatment (100 mg/kg/d) on mechanical allodynia and neuroinflammation was evaluated in rat PIPN model. The expression of pro-inflammatory markers protein and mRNA levels in dorsal root ganglia (DRGs) and spinal cord dorsal horn (SCDH) were measured with Western blot, ELISA and qPCR 10 and 21 days after PIPN induction. Losartan treatment attenuated mechanical allodynia significantly. Paclitaxel induced overexpression of C-C motif chemokine ligand 2 (CCL2), tumour necrosis alpha (TNFα) and interleukin-6 (IL-6) in DRGs, where the presence of macrophages was demonstrated. Neuroinflammatory changes in DRGs were accompanied with glial activation and pro-nociceptive modulators production in SCDH. Losartan significantly attenuated paclitaxel-induced neuroinflammatory changes and induced expression of pro-resolving markers (Arginase 1 and IL-10) indicating a possible shift in macrophage polarization. Considering the safety profile of losartan, acting also as partial PPARγ agonist, it may be considered as a novel treatment strategy for PIPN patients.