Expanding Arsenal against Neurodegenerative Diseases Using Quercetin Based Nanoformulations: Breakthroughs and Bottlenecks

Abstract

Quercetin (Qu), a dietary flavonoid, is obtained from many fruits and vegetables such as coriander, broccoli, capers, asparagus, onion, figs, radish leaves, cranberry, walnuts, and citrus fruits. It has proven its role as a nutraceutical owing to numerous pharmacological effects against various diseases in preclinical studies. Despite these facts, Qu and its nanoparticles are less explored in clinical research as a nutraceutical. The present review covers various neuroprotective actions of Qu against various neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. A literature search was conducted to systematically review the various mechanistic pathways through which Qu elicits its neuroprotective actions and the challenges associated with raw Qu that compromise therapeutic efficacy. The nanoformulations developed to enhance Qu's therapeutic efficacy are also covered. Various ongoing/completed clinical trials related to Qu in treating various diseases, including NDs, are also tabulated. Despite these many successes, the exploration of research on Qu-loaded nanoformulations is limited mostly to preclinical studies, probably due to poor drug loading and stability of the formulation, time-consuming steps involved in the formulation, and their poor scale-up capacity. Hence, future efforts are required in this area to reach Qu nanoformulations to the clinical level.

Keywords: Alzheimer’s disease; Quercetin; antioxidant; neurodegenerative disease; neuroinflammation; novel drug delivery systems.

Fig. (1)

Effects of Qu on the treatment of HD [77].

Fig. (2)

Mechanistic pathways deciphering the effect of Qu against (A) Alzheimer’s disease (AD), (B) Parkinson’s disease (PD), (C) Huntington’s disease (HD), and (D) Amyotrophic lateral sclerosis (ALS).

Fig. (3)

Figure depicting (A) various nanoparticles prepared for Qu and (B) mechanism involved in brain targeting of Qu NDDS upon oral administration. Figure depicting (A) various nanoparticles prepared for Qu and (B) mechanism involved in brain targeting of Qu NDDS upon oral administration. 1. Various NDDS such as NEs, nanoliposome, SLNs, NLCs, polymeric nanoparticles, transferosomes, and niosome; (B) 2. The Qu-loaded NDDS get absorbed by passive diffusion and endocytosis and reach into systemic circulation; 3 These NDDS cross BBB because of their nanometer size.

Fig. (4)

Anti-AD effects of Qu-loaded exosome [92]. (A) Bioavailability study (Ba) Effects of Qu-loaded exosomes in CDK5(pTyr15)/CDK5, Tau (phospho T231)/Tau, cleaved-caspase3/β-actin and cleaved-caspase9/β-actin. (Bb) The image of NFT (blue arrows) on the brain section. (C) Behavioural parameters in MWM test. (D) Representative fluorescence images of C57BL/6 mice brains treated with Qu and Exo-Qu via I.V. injection and I.P. injection.

Fig. (5)

Qu nanoparticles minimize symptoms of AD in cell lines and in vivo studies [90]. [Copyright (2019) American Chemical Society]. (A) Three days observation studies in which observed effects of Qu nanoparticle, polyglutamate aggregation, and reduction in cytotoxicity. (B) Immunoblot assay.

Fig. (6)

Effect of Qu nanoparticles in scopolamine-induced spatial memory deficit for the treatment of AD [114]. (A) Effect of raw Qu and Qu nanoparticles on avoidance test against scopolamine-induced cognitive dysfunction and mental confusion in rat, (B) Effect of Qu and Qu nanoparticles on rectangular maze test for analyzing cognitive function in rat, (C) Histopathology images indicating neuroprotective effects in the normal, control, raw Qu, Qu nanoparticles and standard drug.