Neuroprotective responses of quercetin in regulation of biochemical, structural, and neurobehavioral effects in 28-day oral exposure of iron in rats.

BACKGROUND: Iron is one of the essential metals that functions as a cofactor in various biological cascades in the brain. However, excessive iron accumulation in the brain may lead to neurodegeneration and may show toxic effects. Quercetin, a pigment flavonoid compound, has been proven to be a potent antioxidant and anti-inflammatory that can inhibit lipid peroxidation during metal-induced neurotoxicity. Although iron-induced neuroinflammation and neurodegeneration have been reported in many studies, but the proof for its exact mechanisms needs to be explored. PURPOSE: The key target of the study was to explore the neuroprotective effect of quercetin after oral exposure of iron in rats and explore its underlying molecular mechanisms. RESULTS: The outcomes of the study have shown that oral exposure to ferrous sulfate may modulate behavioral paradigms such as locomotor activity, neuromuscular coordination, and increased anxiety level. The pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), apoptotic protein (caspase 3), beta-amyloid and phosphorylated tau were found to be increased on iron exposure. Also, the expressions of ferritin heavy and light chain, BACE-1 and GFAP expressions were altered. These behavioral, structural, and biochemical alterations in the brain were significantly and dose-dependently reversed by treatment with quercetin. CONCLUSION: The current study provides a fundamental understanding of molecular signaling pathways, and structural proteins implicated in iron-induced neurotoxicity along with the ameliorative effects of quercetin.

Molecular and functional characteristics of receptor-interacting protein kinase 1 (RIPK1) and its therapeutic potential in Alzheimer's disease.

Inflammation and cell death processes positively control the organ homeostasis of an organism. Receptor-interacting protein kinase 1 (RIPK1), a member of the RIPK family, is a crucial regulator of cell death and inflammation, and control homeostasis at the cellular and tissue level. Necroptosis, a programmed form of necrosis-mediated cell death and tumor necrosis factor (TNF)-induced necrotic cell death, is mostly regulated by RIPK1 kinase activity. Thus, RIPK1 has recently emerged as an upstream kinase that controls multiple cellular pathways and participates in regulating inflammation and cell death. All the major cell types in the central nervous system (CNS) have been found to express RIPK1. Selective inhibition of RIPK1 has been shown to prevent neuronal cell death, which could ultimately lead to a significant reduction of neurodegeneration and neuroinflammation. In addition, the kinase structure of RIPK1 is highly conducive to the development of specific pharmacological small-molecule inhibitors. These factors have led to the emergence of RIPK1 as an important therapeutic target for Alzheimer's disease (AD).

Monoclonal antibodies for the management of central nervous system diseases: clinical success and future strategies.

INTRODUCTION: Recombinant monoclonal antibodies (mAbs) are highly selective and effective biologicals with proven utility as therapeutics. mAbs have demonstrated substantial promise in the treatment of several central nervous system diseases. AREAS COVERED: Databases including PubMed and Clinicaltrials.gov were used to identify clinical studies of mAbs involving patients with neurological disorders. This manuscript reviews the current status and recent advances in the development and engineering of therapeutic blood-brain barrier (BBB)-crossing mAbs and their potential in treatment of central nervous system diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), brain tumors, and neuromyelitis optica spectrum disorder (NMSOD). In addition, the clinical implications of recently developed monoclonal antibodies are also discussed, along with the strategies to enhance their BBB permeability. The adverse events associated with the administration of monoclonal antibodies are also presented in the manuscript. EXPERT OPINION: There is growing evidence that supports the therapeutic utility of monoclonal antibodies in central nervous system and neurodegenerative diseases. Several studies have offered evidence of clinical efficacy in AD through use of anti-amyloid beta antibodies and anti-tau passive immunotherapy-based strategies. Additionally, ongoing research trials have produced promising findings for the treatment of brain tumors and NMSOD.

Therapeutic potential of targeting IL-17 and its receptor signaling in neuroinflammation.

T helper 17 cells are thought to significantly contribute to the neuroinflammation process during neurogenerative diseases via their signature cytokine, interleukin (IL)-17. Recently, an emerging key role of IL-17 and its receptors has been documented in inflammatory and autoimmune diseases. The clinical studies conducted on patients with neurodegenerative disease have also shown an increase in IL-17 levels in serum as well as cerebrospinal fluid samples. Therapeutic targeting of either IL-17 receptors or direct IL-17 neutralizing antibodies has shown a promising preclinical and clinical proof of concept for treating chronic autoimmune neurodegenerative diseases such as multiple sclerosis. Thus, IL-17 and its receptors have a central role in regulation of neuroinflammation and can be considered as one of the major therapeutic targets in chronic neuroinflammatory diseases.