Asiatic acid attenuated apoptotic and inflammatory stress in the striatum of MPTP-treated mice

Abstract

The effects of post-treatments with asiatic acid (AA) at 20, 40 or 80 mg per kg BW per day against apoptotic, oxidative and inflammatory injury in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were examined. The results showed that AA supplements at 40 and 80 mg per kg BW per day increased AA deposit in the striatum, increased glutathione content and decreased reactive oxygen species production in the striatum. AA supplements at 20-80 mg per kg BW per day dose-dependently lowered striatal levels of nitric oxide, 3-nitrotyrosine, interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and prostaglandin E2. AA supplements at 40 and 80 mg per kg BW per day down-regulated striatal p47(phox) and gp91(phox) expression; but, at three test doses suppressed striatal expression of inducible nitric oxide synthase and cyclooxygenase-2. AA post-treatments at 40 and 80 mg per kg BW per day enhanced Bcl-2 expression, and lowered Bax, apoptosis-inducing factor and caspase-3 expression in the striatum. AA at 20-80 mg per kg BW per day up-regulated striatal tyrosine hydroxylase expression, and suppressed Toll-like receptors (TLR)2 and nuclear factor kappa B p65 expression. AA treatments at 40 and 80 mg per kg BW per day decreased striatal expression of α-synuclein and TLR4, increased striatal levels of dopamine, brain-derived nerve growth factor and glial cell line-derived neurotrophic factor. These novel findings suggest that asiatic acid is a potent nutraceutical agent against the progression of Parkinson's disease.

Molecular Targets Involved in the Neuroprotection Mediated by Terpenoids

“…Antioxidant and antiapoptotic effects were also involved in the therapeutic potential of asiatic acid in PD. These effects were observed in rotenone-induced apoptosis in SH-SYS5Y cells [115,116] and further confirmed in MPTP-treated mice, as an in vivo model of PD [117]. After oral administration of asiatic acid, an increase in striatal glutathione levels, decrease in ROS production, and modulation of the apoptotic process, together with anti-inflammatory effects, were observed.…”

“…After oral administration of asiatic acid, an increase in striatal glutathione levels, decrease in ROS production, and modulation of the apoptotic process, together with anti-inflammatory effects, were observed. These effects could be explained by the suppression in the striatal expression of toll-like receptors (TLRs) and NF-κB [117]. Asiatic acid also improved dopamine striatal levels, thus ameliorating dopaminergic neurodegeneration, along with a marked neurotrophic effect by increasing the neurotrophins BDNF and glial cell line-derived GDNF [117] and its tyrosine kinase receptors (TrKB) [118].…”

“…These effects could be explained by the suppression in the striatal expression of toll-like receptors (TLRs) and NF-κB [117]. Asiatic acid also improved dopamine striatal levels, thus ameliorating dopaminergic neurodegeneration, along with a marked neurotrophic effect by increasing the neurotrophins BDNF and glial cell line-derived GDNF [117] and its tyrosine kinase receptors (TrKB) [118]. Survival signaling pathways such us MAPKs and PI3K/Akt/mTOR were also involved in the neuroprotective effect offered by asiatic acid on dopaminergic neurons in this PD model.…”

Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise

“…In a recent study, Nataraj et al ( 2017 ) demonstrated the antioxidant, cytoprotective and antiapoptotic activities of AA against rotenone-induced cytotoxicity in SH-SY5Y cells. The in vitro results were further confirmed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice (Chao et al, 2016 ). AA found bioavailable in the striatum and reduced free radical generation along with raised glutathione levels.…”

“…AA was well-tolerated up to a dose of 75 mg/kg (Lee et al, 2012 ). The bioavailability of AA in the plasma, brain, heart, liver, kidney, colon and bladder is more when fed with AA containing fruits and vegetables for several weeks (Yin et al, 2012 ; Chao et al, 2016 ).…”