Nicotine alleviates MPTP-induced nigrostriatal damage through modulation of JNK and ERK signaling pathways in the mice model of Parkinson’s disease

Abstract

Introduction: Nicotine (Nic) has previously been proven to reduce neurodegeneration in the models of Parkinson’s disease (PD). The present study is intended to investigate the detailed mechanisms related to the potential neuroprotective effects of Nic in vivo.Methods: We established a PD model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced C57BL6 mice (25 mg/kg/d, 5 d, i.p.) to investigate the neuropharmacological modulation of Nic pretreatment (2.5 mg/kg/d, 5 d, i.p., 30 min before MPTP injection) from the perspectives of neurobehavioral assessment, the pathological alterations, microglial cell inflammation and MAPK signaling pathways in specific brain regions.Results: The open field test, elevated plus maze, rotarod and traction test suggested that Nic pretreatment could significantly improve MPTP-induced motor impairment and had an anxiolytic effect. Nic was found to improve neuroapoptosis, enhance tyrosine hydroxylase activity, and reduce the accumulation of the phosphorylated α-synuclein in the substantia nigra and striatal regions of PD mice by TUNEL and immunohistochemical assays. Immuno-fluorescent method for labeling Iba1 and CD68 indicated that Nic remarkably alleviates the activation of microglia which represents the M1 polarization state in the mice brain under MPTP stimulation. No significant difference in the expression of p38/MAPK pathway was found in the nigrostriatal regions, while Nic could significantly inhibit the elevated p-JNK/JNK ratio and increase the declined p-ERK/ERK ratio in the substantia nigra of MPTP-exposed brains, which was further confirmed by the pretreatment of CYP2A5 inhibitor to decline the metabolic activity of Nic.Discussion: The molecular signaling mechanism by which Nic exerts its neuroprotective effects against PD may be achieved by regulating the JNK and ERK signaling pathways in the nigra-striatum related brain regions.

Restoration of MPTP-induced dopamine and tyrosine hydroxylase depletion in the mouse brain through ethanol and nicotine

“…Our results align with several previous studies demonstrating that Nic can increase DA and its metabolites, DOPAC and HVA, in the brains of MPTP-treated mice (Janson et al, 1992;Gao et al, 1998). A similar increase in TH has been noted following Nic administration in mice with Parkinsonism induced by MPTP (Parain et al, 2003;Ruan et al, 2023). There are two possible ways to minimize MPTP neurotoxicity: 1) by inhibiting the formation of the active neurotoxin MPP + from MPTP (Heikkila et al, 1984) and 2) by blocking the uptake of MPP + into the DA neurons (Javitch et al, 1985;Sundström et al, 1986).…”

Neuroprotective mechanism of salvianolic acid B against cerebral ischemia–reperfusion injury in mice through downregulation of TLR4, p‐p38MAPK, p‐JNK, NF‐κB, and IL‐1β

“…[26][27][28] Previous studies have shown that cerebral ischemia is closely related to p38MAPK and JNKs. 8,29 As p38MAPK activation is involved in ischemia-induced neurological injury, blocking it may protect brain tissue from ischemia damage by decreasing the production of inflammatory mediators and blocking the inflammatory process. 8 Additionally, inhibiting JNK activation protects against cell death following ischemia.…”

Neuroprotective effect of green tea extract (-)-epigallocatechin-3-gallate in a preformed fibril-induced mouse model of Parkinson’s disease

“…The next day the mice were placed on the stationary rotating rod device and the speed was increased from 5 to 40 rpm/min within 300 s. The time from start to drop was recorded and repeated three times for each mouse. The suspension experimental apparatus was constructed by fixing a smooth wire with a diameter of 1.5 mm and a length of 30 cm at a height of 50 cm above the ground on two parallel pieces of cardboard using a glue gun [ 24 ]. The two front mouse paws were placed in the mid-point of the 30 cm horizontal wire.…”