Nuclear Factor Kappa B: A Nobel Therapeutic Target of Flavonoids Against Parkinson's Disease.

Parkinson's disease (PD), the most common brain-related neurodegenerative disorder, is comprised of several pathophysiological mechanisms, such as mitochondrial dysfunction, neuroinflammation, aggregation of misfolded alpha-synuclein, and synaptic loss in the substantia nigra pars compacta region of the midbrain. Misfolded alpha-synuclein, originating from damaged neurons, triggers a series of signaling pathways in both glial and neuronal cells. Activation of such events results in the production and expression of several proinflammatory cytokines via the activation of the nuclear factor κB (NF-κB) signaling pathway. Consequently, this cascade of events worsens the neurodegenerative processes, particularly in conditions, such as PD and synucleinopathies. Microglia, astrocytes, and neurons are just a few of the many cells and tissues that express the NF-κB family of inducible types of transcription factors. The dual role of NF-κB activation can be crucial for neuronal survival, although the classical NF-κB pathway is important for controlling the generation of inflammatory mediators during neuroinflammation. Modulating NF-κB-associated pathways through the selective action of several agents holds promise for mitigating dopaminergic neuronal degeneration and PD. Several naturally occurring compounds in medicinal plants can be an effective treatment option in attenuating PD-associated dopaminergic neuronal loss via selectively modifying the NF-κB-mediated signaling pathways. Recently, flavonoids have gained notable attention from researchers because of their remarkable anti-neuroinflammatory activity and significant antioxidant properties in numerous neurodegenerative disorders, including PD. Several subclasses of flavonoids, including flavones, flavonols, isoflavones, and anthocyanins, have been evaluated for neuroprotective effects against in vitro and in vivo models of PD. In this aspect, the present review highlights the pathological role of NF-κB in the progression of PD and investigates the therapeutic potential of natural flavonoids targeting the NF-κB signaling pathway for the prevention and management of PD-like manifestations with a comprehensive list for further reference. Available facts strongly support that bioactive flavonoids could be considered in food and/or as lead pharmacophores for the treatment of neuroinflammation-mediated PD. Furthermore, natural flavonoids having potent pharmacological properties could be helpful in enhancing the economy of countries that cultivate medicinal plants yielding bioactive flavonoids on a large scale.

Pre-clinical Evidence-based Neuroprotective Potential of Naringin against Alzheimer's Disease-like Pathology: A Comprehensive Review.

Neurodegenerative disorders (NDs) are a group of progressive, chronic, and disabling disorders that are highly prevalent and the incidence is on a constant rise globally. Alzheimer's disease (AD), one of the most common neurodegenerative disorders is hallmarked by cognitive impairment, amyloid-ß (Aß) deposition, hyperphosphorylation of tau protein, cholinergic dysfunction, mitochondrial toxicity, and neurodegeneration. Available therapeutic agents only provide symptomatic relief and their use are limited due to serious side effects. Recent research has recognized flavonoids as potential multi-target biomolecules that can reduce the pathogenesis of AD. Naringin, a natural citrus flavonoid has been traditionally used to treat various NDs including AD, and has gained special attention because exhibits a neuroprotective effect by affecting numerous signaling pathways with minimum adverse effects. Naringin reduces deposition of Aß, hyperphosphorylation of tau protein, cholinergic dysfunction, oxidative stress burden, mitochondrial toxicity, the activity of glutamate receptors, and apoptosis of the neuronal cells. Additionally, it reduces the expression of phosphorylated-P38/P38 and the NF-κB signaling pathway, showing that a wide range of molecular targets is involved in naringin's neuroprotective action. The present study describes the possible pharmacological targets, signaling pathways, and molecular mechanisms of naringin involved in neuroprotection against AD-like pathology. Based on the above pre-clinical reports it can be concluded that naringin could be an alternative therapeutic agent for the management of AD-like manifestation. Thus, there is a strong recommendation to perform more preclinical and clinical studies to develop naringin as a novel molecule that could be a multi-target drug to counteract AD.

A Research Update on Exendin-4 as a Novel Molecule Against Parkinson's Disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, and its consequences severely influence the quality of a patient's life and mobility. PD is characterized by bradykinesias with tremors and/or rigidity. Pathophysiologically, PD is associated with the gradual degeneration of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, neuroinflammation, increased accumulation of the alpha (α)-synuclein, overburden of oxidative stress, and mitochondrial dysfunction. To date, there are no effective therapies with underlying shreds of evidence that alters the progression of PD. Exendin-4, a glucagon-like peptide 1 (GLP-1) receptor agonist, has gained attention for its tremendous neuroprotective potential against numerous neurodegenerative disorders, including PD. Further, several pieces of research evidence have suggested the beneficial role of Exendin-4 in PD-like experimental models. The present review article highlights the preclinical and clinical evidence of the therapeutic benefits of Exendin-4 against PD. Exendin-4 reverses the PD-like symptoms in experimental animals by dramatically minimizing the loss of dopaminergic neuronal and accumulation of α-synuclein in the PD-like brain. Further, it also reduces the mitochondrial toxicity and expression of pro-inflammatory mediators such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß. These observations designate that Exendin-4 is a multifactorial compound that could be considered a safe, effective, and new ingredient for developing clinically useful pharmacotherapy for managing PD-like manifestations.