Asiatic Acid Attenuated Aluminum Chloride-Induced Tau Pathology, Oxidative Stress and Apoptosis Via AKT/GSK-3ß Signaling Pathway in Wistar Rats.

Asiatic acid (AA), a triterpenoid present in Centella asiatica, possesses the ability to cross blood brain barrier and received considerable attention for its neuroprotective role. We have reported the benefit of AA against aluminum chloride (AlCl3)-induced amyloid pathology, enhanced acetylcholine esterase (AChE) activity, and inflammation in Alzheimer's disease (AD) like model rats. Based on that, to find the exact mechanism of action of AA, the present study was designed to evaluate the oxidative stress, tau pathology, apoptosis, and Akt/GSK3ß signaling pathway on AlCl3-induced neurotoxicity in Wistar rats. AD-like pathology was induced by oral administration of AlCl3 (100 mg/kg b.w.) for 6 weeks, which demonstrated a significant reduction in spatial memory performance, anxiety, and motor dysfunction and diminished the expression of cyclin-dependent kinase 5 (CDK 5-enzyme implicated in the phosphorylation of tau proteins), pTau, oxidative stress, and apoptosis, whereas oral ingestion of AA (75 mg/kg b.w.) for 7 weeks attenuated the above-said indices, which could be by activating Akt/GSK3ß pathway. Current results suggested that AA could be able to modulate various pathological features of AD and could hold promise in AD treatment.

Amelioration of Aluminum Maltolate-Induced Inflammation and Endoplasmic Reticulum Stress-Mediated Apoptosis by Tannoid Principles of Emblica officinalis in Neuronal Cellular Model.

The neuroprotective role of tannoid principles of Emblica officinalis (EoT), an Indian and Chinese traditional medicinal plant against memory loss in aluminum chloride-induced in vivo model of Alzheimer's disease through attenuating AChE activity, oxidative stress, amyloid and tau toxicity, and apoptosis, was recently reported in our lab. However, to further elucidate the mechanism of neuroprotective effect of EoT, the current study was designed to evaluate endoplasmic reticulum stress-suppressing and anti-inflammatory role of EoT in PC 12 and SH-SY 5Y cells. These cells were divided into four groups: control (aluminum maltolate (Al(mal)3), EoT + Al(mal)3, and EoT alone based on 3-(4, 5-dimethyl 2-yl)-2, and 5-diphenyltetrazolium bromide (MTT) assay. EoT significantly reduced Al(mal)3-induced cell death and attenuated ROS, mitochondrial membrane dysfunction, and apoptosis (protein expressions of Bax; Bcl-2; cleaved caspases 3, 6, 9, 12; and cytochrome c) by regulating endoplasmic reticulum stress (PKR-like ER kinase (PERK), α subunit of eukaryotic initiation factor 2 (EIF2-α), C/EBP-homologous protein (CHOP), and high-mobility group box 1 protein (HMGB1)). Moreover, inflammatory response (NF-κB, IL-1ß, IL-6, and TNF-α) and Aß toxicity (Aß1-42) triggered by Al(mal)3 was significantly normalized by EoT. Our results suggested that EoT could be a possible/promising and novel therapeutic lead against Al-induced neurotoxicity. However, further extensive research is needed to prove its efficacy in clinical studies.

Neuroprotective role of Asiatic acid in aluminium chloride induced rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia, characterized by memory loss, cognitive impairment and personality disorders accompanied by diffuse structural abnormalities in the brain of elderly people. The current investigation explored the neuroprotective potential of asiatic acid (AA), a natural triterpene of Centella asiatica on aluminium chloride (AlCl3) induced rat model of AD. Oral administration of AlCl3 (100 mg/kg b.w.) for 42 days significantly elevated the levels of Al, activity of acetyl cholinesterase and expressions of amyloid precursor protein, amyloid beta1-42, beta and gamma secretases, glial fibrillary acidic protein, ionized calcium binding adaptor molecule 1, interleukins -1ß, 6, 4, 2, tumor necrosis factor alpha, inducible nitric oxide synthase, nuclear factor- k beta and cyclooxygenase-2 in the hippocampus and cortex  compared to the control group. Our observations suggested that AA treatment mitigated AlCl3 induced AD associated pathologies, which might be due to its multiple pharmacological actions. Further studies are necessary in order to explore the link between AlCl3-mediated oxidative stress and associated apoptosis to establish its neuroprotective role in AD.

Asiatic acid nullified aluminium toxicity in in vitro model of Alzheimer's disease.

Aluminium (Al) is a ubiquitously distributed environmental toxicant that lacks biological functions; however, its accumulation in the brain has been demonstrated to be linked to several neuropathological conditions particularly Alzheimer's disease (AD). Asiatic acid (AA), a triterpene extracted from Centella asiatica, has been reported to cross the blood brain barrier and also displayed antioxidant and neuroprotective activities. The present study was aimed to explore the neuroprotective effect of AA against aluminium maltolate (Al(mal)3) induced neurotoxicity by assessing cell viability, mitochondrial membrane potential, levels of reactive oxygen species (ROS), DNA damage and apoptosis (Hoechst and dual staining, comet assay; expressions of pro-apoptotic, anti-apoptotic and signaling indices) via AKT/GSK-3ß signaling pathway in SH-SY 5Y  neuroblastoma cells. Pre-treatment with AA significantly enhanced cell viability, attenuated rotenone-induced ROS, mitochondrial membrane dysfunction and apoptosis regulating AKT/GSK-3ß signaling pathway. Downregulation of Al induced neurodegeneration may be one of the approaches to control the impairment of metal ion homeostasis leading to neuronal injury in  early development of AD. However, more extensive work in animal model is desirable to confirm its neuroprotective action.