Review
Therapeutic potential of naringin in neurological disorders

https://doi.org/10.1016/j.fct.2019.110646Get rights and content

Highlights

  • Neurological illnesses are multifactorial incurable debilitating disorders that may cause neurodegeneration.

  • Neurological illnesses affect approximately 30 million people around the world.

  • Effective management of such disorders remains a global challenge.

  • Naringin has been shown possess outstanding therapeutic potential as a neuroprotective agent.

  • Naringin affects multiple signaling pathways in its neuropharmacological efficacy.

  • Naringin might be a potential candidate for neurotherapeutics.

Abstract

Neurological illnesses are multifactorial incurable debilitating disorders that may cause neurodegeneration. These diseases influence approximately 30 million people around the world. Despite several therapies, effective management of such disorders remains a global challenge. Thus, natural products might offer an alternative therapy for the treatment of various neurological disorders. Polyphenols, such as curcumin, resveratrol, myricetin, mangiferin and naringin (NRG) have been shown to possess promising potential in the treatment of neurogenerative illness. In this review, we have targeted the therapeutic potential of naringin as a neuroprotective agent. The overall neuroprotective effects and different possible underlying mechanisms related to NRG are discussed. In light of the strong evidence for the neuropharmacological efficacy of NRG in various experimental paradigms, it is concluded that this molecule should be further considered and studied as a potential candidate for neurotherapeutics, focusing on mechanistic and clinical trials to ascertain its efficacy.

Introduction

Alzheimer's malady (AD), Parkinson's ailment, Ischemic brain damage and Glioblastoma are neurodegenerative disorders that influences the central nervous system. The available medicines for these disorders ameliorate the symptoms but cannot cure the disease altogether. AD results, cerebrum shrinkage, cognitive deformities, social and mental issues because of ROS, collection of extracellular Amyloid-beta 42 plaques, intracellular hyper-phosphorylated Tau tangles. Until this point in time, there is no direct remedy for AD. FDA affirmed medicate routine of (anti-inflammatory and cholinesterase inhibitors) like atorvastatin, ibuprofen, and rosiglitazone for simply symptomatic alleviation yet don't fix the illness itself and have side-reactions. Subsequently, there is a need of drug, which has less symptoms and can treat the ailment by anticipating the neuronal cell demise. The traditional herbal medications are the only choice with less side-reactions, better efficacy and economical than the engineered medications. Natural products like peptides (Lunasin), Polyphenols (Curcumin, Resveratrol) Flavonoids (Quercitin, Catechin, Kaempferol) Alkaloids (Huperzine A, Berberine) and terpenes (Gensenoside, Ginkgolides, Platycodin D) are potential restorative possibility for the AD due to having anticholinesterase, anti-inflammatory, antioxidant, and neuroprotective capacity (Deshpande et al., 2019).

Parkinson's illness (PD) is neurodegenerative turmoil with oxidative pressure, apoptosis, mitochondrial dysfunction and inflammation. Right now, the current pharmacological medications for PD can't improve generally the degenerative procedure of dopaminergic neurons and have various reactions. Concentrates of Valeriana officinalis, Valeriana wallichii, Passiflora incarnata, Passiflora cincinnata, Hypericum perforatum, Ginkgo biloba, Ginseng and Flavonoids (Baicalein, Luteolin, Quercetin, apigenin, Rutin, Kaempferol, hesperidin) are potential restorative possibility for the PD due to having antioxidant, hostile to apoptotic, anti-inflammatory impacts. Despite the fact that the utilization of natural compounds for the neurological issue has been considered as a sheltered methodology, they are still a long way from being standard medicines, because of the absence of controlled clinical examinations that could verify both their high adequacy and wellbeing. Subsequently, better structured and progressively thorough clinical preliminaries are required before they can be set up as remedial compounds (Corona, 2018).

Ischemic brain injury is one of the main sources of death worldwide and has pulled in a great deal of consideration in the field of medication disclosure. Cerebral ischemia is a complex obsessive procedure including a progression of components, including free radicals’ generation, oxidative pressure, disturbance of the membrane work, release of neurotransmitters and apoptosis. Thrombolytic treatment is the best restorative technique, yet the advantages are a long way from being outright. Expanded consideration in the field of medication disclosure has been centered around utilizing natural compounds having all the earmarks of being a promising remedial choice for cerebral ischemia. Resveratrol, Ginkgo biloba, Curcumin, Epigallocatechin-3-gallate, Baicalin, Ligustilide, Tanshinone, Wogonin, Paeonol, Scutellarin are Herbal lead particles under scrutiny (Ghosh et al., 2014).

Glioblastoma is a standout amongst the most forceful dangerous tumors with a generally grim survival averaging one year in spite of multimodality helpful intercessions including medical procedure, radiotherapy and associative and adjuvant chemotherapy. Scarcely any medications are FDA affirmed for glioblastoma, and the expansion of temozolomide to standard treatment builds the middle survival by just 2.5 months. Targeted treatment seemed promising in vitro monolayer cultures, however disillusioned in preclinical and clinical preliminaries, halfway because of the poor infiltration of medications through blood cerebrum hindrance. Because of the disappointment of traditional chemotherapies and focused on medications, examine endeavors concentrating on the utilization of less lethal specialists have expanded. Glioblastoma, the most widely recognized threatening mind tumor in grown-ups, stays serious with a hopeless middle survival. Notwithstanding various endeavors there have been not many FDA affirmed drugs for its treatment, which are not all around effective. Strikingly, numerous compounds from natural sources to be specific resveratrol, betulinic acid, icariin, quercetin, curcumin, Withaferin A, thymoquinone, cucurbitacins, Toosendanin and diosquinone are repoted to have defensive impacts in glioblastoma. An abundance of preclinical information exists to help further examination utilizing natural products in glioblastoma. Forthcoming randomized clinical preliminaries must be done to investigate the utilization of adjunctive natural treatment in better focusing on obstruction and synergistically enhancing standard medications (Vengoji et al., 2018).

Epilepsy is a standout amongst the most well-known neurological disorders around the world, with around 80 percent of cases thought to be in creating countries where it is for the most part connected to superstition. The restricted supply, low viability and side reactions of antiepileptic drugs involves significant concern. Herbal prescription has dependably been generally part of treatment of epilepsy. Animal models have been utilized since days of yore to test new medications, and are constantly winding up progressively modern as innovation and scientific getting advances. Uncaria rhynchophylla, Desmodium triflorum, Viscum album, Morus alba, Berberis integerrima, Mussaenda philippica, Justicia pectoralis, Gladiolus dalenii, Ficus. religiosa, Withania somnifera, Lobelia nicotianaefolia, Marsilea quadrifolia, Passiflora incarnata, Mondia whitei, Gastrodia elata are potential anti epileptic natural remedies tested in animal models (Manchishi, 2018).

Naringin (NRG) is a well-studied plant secondary metabolite. It was found first by De Vry in grapefruit blossoms in 1857 (Rangaswami and Seshadri, 1939). The name NRG is likely derived from “narangiʼ meaning “orange” (Sinclair, 1972). The chemical structure of NRG was originally characterized by Asahina and Inubuse in 1928 (Asahina and Inubuse, 1928), represented in Fig. 1. NRG is sparingly soluble in aqueous buffers, and has weakly basic nature (Tomasik, 2003). Pharmacokinetically, NRG is converted to naringenin upon phase-I metabolism, with subsequent metabolism to p-coumaric acid or p-hydroxy benzoic acid (Bharti et al., 2014).

NRG can be isolated from several plant families and species. When tested in various pharmacological assays, NRG has been shown to possess therapeutic efficacy against cancer, allergy, hypertension, diabetes and asthma. It is also protective in liver disorders and gastrointestinal tract ailments. In recent time, we already have explored the therapeutic potential plant flavonoids Nabavi et al. (2018a); Nabavi et al. (2018b); Khan et al. (2019); (Rengasamy et al., 2019). Similarly, it has shown efficacy in several neurological disorders. The movement of neuroprotective drugs is constrained by the blood-cerebrum boundary. The revelation and advancement of medications for neurological sicknesses, restricted significantly because of medication selectivity presented by the BBB, prompting the neglect of most medication particles in spite of their intensity in vitro. NRG showed the capacity to cross the BBB which is accounted for to tie to CRMP - 2 (Collapsin Response Mediator Protein - 2), modifies structure of CRMP - 2 and decreases phosphorylation. The extensive binding capability of NRG is bolstered by the ideal negative binding energy. Furthermore, dynamic site deposits, for example, Glu 343, Thr 349, and Arg 75 were seen to contribute for the same purpose. NRG-CRMP-2 communication, combined with physicochemical properties (molecular weight, lipophilicity, polar surface zone, charge, sub-atomic flexibility, number of rotatable bond and hydrogen bonding) utilizing for an appropriate CNS medicate. So, NRG can enter the BBB and achieve the cerebrum by means of passive diffusion and applies its neuroprotective exercises (Lawal et al., 2018). This review is aimed at evaluating the available literature on the neuroprotective efficacy of this compound with underlying possible mechanism(s).

Section snippets

Naringin sources and structure

NRG has been isolated from several plant families. A summary of these plant species is shown in Table 1. Naringin is a disaccharide derivative that is (S)-naringenin substituted by a 2-O-(α-L-rhamnopyranosyl)-beta-D-glucopyranosyl moiety at position 7 via a glycosidic linkage. It is a dihydroxyflavanone, a member of 4′-hydroxyflavanones, a (2S)-flavan-4-one and a neohesperidoside (National Center for Biotechnology Information, 2019). Naringin is 4′,5,7- trihydroxyflavanone- 7-rhamnoglucoside, a

Therapeutic potential of naringin

NRG has shown therapeutic potential in various human disorders (Fig. 2). The hypocholesterolemic effects of NRG are characterized as antiadipogenic and antiatherogenic (Richard et al., 2013), decreasing the esterification of cholesterol and the bioavailability of lipids to assemble lipoprotein (Cho et al., 2011) via inhibition of hepatic HMG-Coenzyme A reductase and sterol O-acyltransferase (Sui et al., 2018). NRG has been also shown to decrease infarct size of myocardium Rani et al. (2013) (

Alzheimer's disease

Alzheimer's disease (AD) is widely recognized neurodegenerative illness characterized by memory loss and neuroinflammation (Yang et al., 2018). NRG has shown therapeutic potential against AD (Fig. 3). Aluminium chloride has been commonly used to experimentally produce AD-like symptoms. Chronic administration of NRG in aluminum-treated rats enhanced cognitive execution and reduced mitochondrial oxidative damage (Prakash et al., 2013). In another study in mice, D-galactose administration

Side effects of naringin

NRG 1250 mg/kg/day orally following each day to Sprague–Dawley rats for a half year did not cause any lethality or dangerous clinical signs and changes in the two sexes of rats aside from slight body weight decline and reversible male pattern baldness, which recovered after a month. Utilizing the body surface region standardization strategy, 1250 mg/kg NRG in rat thinks about to 200 mg/kg in individuals, or 12 g for a 60 kg human (Li et al., 2014b). NRG has a LD50 estimation of 2000 mg/kg and

Acknowledgements

Michael Aschner was partially supported by grants from the National Institute of Environmental Health Sciences (NIEHS R01ES07331, NIEHS R01ES10563 and NIEHS R01ES020852).

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