Antioxidant and Anti-Inflammatory Effects of Citrus Flavonoid Hesperetin: Special Focus on Neurological Disorders

Abstract

Neurodegenerative disorders have emerged as a serious health issue in the current era. The most common neurodegenerative disorders are Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS). These diseases involve progressive impairment of neurodegeneration and memory impairment. A wide range of compounds have been identified as potential neuroprotective agents against different models of neurodegeneration both in vivo and in vitro. Hesperetin, a flavanone class of citrus flavonoid, is a derivative of hesperidin found in citrus fruits such as oranges, grapes, and lemons. It has been extensively reported that hesperetin exerts neuroprotective effects in experimental models of neurodegenerative diseases. In this systematic review, we have compiled all the studies conducted on hesperetin in both in vivo and in vitro models of neurodegeneration. Here, we have used an approach to lessen the bias in each study, providing a least biased, broad understanding of findings and impartial conclusions of the strength of evidence and the reliability of findings. In this review, we collected different papers from a wide range of journals describing the beneficial effects of hesperetin on animal models of neurodegeneration. Our results demonstrated consistent neuroprotective effects of hesperetin against different models of neurodegeneration. In addition, we have summarized its underlying mechanisms. This study provides the foundations for future studies and recommendations of further mechanistic approaches to conduct preclinical studies on hesperetin in different models.

Keywords: Alzheimer’s disease; Parkinson’s disease; hesperetin; neurodegeneration; neuroprotection.

Figure 1

Pathogenesis of neurodegenerative diseases. A diagram showing the role of activated astrocytes, microglia, neuroinflammation, and elevated oxidative stress in the procession of neurodegeneration. Aβ: Amyloid beta, ROS: Reactive oxygen species, Nrf2: Nuclear factor-2 related factor-2, HO-1: Heme-oxygenase-1, PSD-95: postsynaptic density protein 95, SNAP25: Synaptosome Associated Protein 25, Syn: Syntaxin.

Figure 2

Chemical Structures of different types of flavonoids and hesperetin. a. Chemical structure of flavan, flavonol, flavone, isoflavone, flavon-3-ols, and anthocyanidin. b. Chemical structure of hesperetin.

Figure 3

Role of flavonoids in the management of neurodegenerative diseases. A diagram showing the role of hesperetin in the management of neurodegenerative diseases. The image highlights the role of flavonoids against aging, Parkinson’s disease, and Alzheimer’s disease-induced neurodegenerative conditions. As with neurodegeneration, there is an elevation in the level of reactive oxygen species, which facilitates the neuroinflammation by activating the NF-kB and MAP kinases, and release of inflammatory cytokines and neurodegeneration. Interestingly, these effects were markedly reduced with the administration of flavonoids.

Figure 4

Role of hesperetin in the management of AD-like pathological changes in mice brains. A simple illustration showing the effects of Aβ and LPS on the mice’s brains. The injection of Aβ and LPS into the mice by intracerebroventricular or intraperitoneal injection hesperetin induces oxidative stress, amyloidogenesis, neuroinflammation, and cognitive dysfunction in the mice brains. These effects were markedly reduced with the administration of hesperetin.

Figure 5

Role of hesperetin in the management of PD-like changes in the mice brains. A simple diagram showing the effects of 6-hydroxydopamine, a potent and known environmental neurotoxin that is used for modeling of PD-like symptoms in mice. Unilateral injection of 6-hydroxydopamine into the striatum of the mice induced oxidative stress, neuroinflammation, and motor dysfunction in mice. These effects were markedly reduced with the administration of hesperetin.

Figure 6

Effects of hesperetin against neuroinflammatory mediators. A diagram showing the effects of hesperetin against the inflammatory mediators in different models of neurodegenerative diseases.