Resveratrol: A potential therapeutic natural polyphenol for neurodegenerative diseases associated with mitochondrial dysfunction

Abstract

Most polyphenols can cross blood-brain barrier, therefore, they are widely utilized in the treatment of various neurodegenerative diseases (ND). Resveratrol, a natural polyphenol contained in blueberry, grapes, mulberry, etc., is well documented to exhibit potent neuroprotective activity against different ND by mitochondria modulation approach. Mitochondrial function impairment is the most common etiology and pathological process in various neurodegenerative disorders, viz. Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Nowadays these ND associated with mitochondrial dysfunction have become a major threat to public health as well as health care systems in terms of financial burden. Currently available therapies for ND are limited to symptomatic cures and have inevitable toxic effects. Therefore, there is a strict requirement for a safe and highly effective drug treatment developed from natural compounds. The current review provides updated information about the potential of resveratrol to target mitochondria in the treatment of ND.

Keywords: Alzheimer’s disease; Parkinson’s disease; neurodegenerative diseases; polyphenol; resveratrol.

FIGURE 1

Structure of RES.

FIGURE 2

Neuroprotective effect of RES in AD pathogenesis. Oxidative stress leads to formation of ROS especially, iNOS and COX-2, which plays a vital role in cellular apoptosis. RES decreases the level of iNOS and COX-2 and stimulate the HO-1 level to inhibit oxidative damage. RES reduces oxidative stress by decreasing the Nox4 expression and elevating the level of ROS inactivating enzymes, i.e., SOD1 and GPx. RES activates SIRT1 followed by inhibition of p53 and FOXO to attenuate BAX and JNK dependent apoptosis and neuronal cell death. APP, amyloid precursor protein; BAX, Bcl-2-associated X protein; COX-2, cyclooxygenase-2; HO-1, heme oxygenase-1; iNOS, inducing nitric oxide synthase; JNK, Jun N-terminal kinases; Nox4, NADPH oxidase 4; ROS, reactive oxygen species; SIRT1, sirtuin 1.

FIGURE 3

Neuroprotective effect of RES in PD pathogenesis via reversal of mitochondrial impairment by (A) activation of AMPK and (B) inhibition of mTOR and ULK1 leads to autophagy/mitophagy by recruiting autophagosomes followed by inhibition of mitochondrial dependent apoptosis; (C) activation of SIRT-1-AMPK signalling pathway enhances the process of mitochondrial biogenesis by persuading PGC-1α, Nrf1/2, and TFAM; (D) reduction in aggregation of α-syn aggregation; (E) scavenging action on cellular ROS and activation of endogenous antioxidant enzymatic activities. Normal physiology of mitochondrial bioenergetics comprises the mitochondrial OXPHOS system, exist on the inner membrane, which generates ATP to fulfil the cellular energy requirements. During the OXPHOS process, leakage of electrons takes place from mitochondrial complexes I and III, and generates the O2 •− byproducts. These radicals disrupt the Ca²⁺ homeostasis, induces damaging effect on mtDNA and, increases oxidative stress as well as apoptosis associated with mitochondria. Antioxidant mechanisms of mitochondria involves ROS-scavenging enzyme SOD2, GPx and PRx. AMPK, adenosine monophosphate-activated protein kinase; Bak, B cell lymphoma 2 (Bcl-2) homologous antagonist killer; Bax, Bcl-2-associated X protein; cyt c, cytochrome c; GPx, glutathione peroxidase; HO-1, heme oxygenase-1; IMS, intermembrane space; MAC, mitochondrial apoptosis-induced channel; MCU, mitochondrial calcium uniporter; Mn-SOD (SOD2), manganese superoxide dismutase; MOMP, mitochondrial outer membrane permeabilization; mPTP, mitochondrial permeability transition pore; mtDNA, mitochondrial DNA; mTOR, mechanistic (or mammalian) target of rapamycin; NCLX, the mitochondrial Na/Li/Ca exchanger; Nrf1/2, nuclear respiratory factor 1 and 2; O2 •−, superoxide radical; OXPHOS, oxidative phosphorylation; PGC-1α, peroxisome proliferator-activated receptor coactivator-1α; PRx, peroxiredoxins (scavenger and antioxidant) ROS, reactive oxidative species; SIRT-1, sirtuin 1; SOD1/2, superoxide dismutase; TFAM, mitochondrial transcription factor A; ULK1, Unc-51 like kinase 1; VDAC, voltage-dependent anion-selective channel; α-syn, α-synuclein.