Phytochemicals against TNFα-Mediated Neuroinflammatory Diseases

Abstract

Tumor necrosis factor-alpha (TNF-α) is a well-known pro-inflammatory cytokine responsible for the modulation of the immune system. TNF-α plays a critical role in almost every type of inflammatory disorder, including central nervous system (CNS) diseases. Although TNF-α is a well-studied component of inflammatory responses, its functioning in diverse cell types is still unclear. TNF-α functions through its two main receptors: tumor necrosis factor receptor 1 and 2 (TNFR1, TNFR2), also known as p55 and p75, respectively. Normally, the functions of soluble TNF-α-induced TNFR1 activation are reported to be pro-inflammatory and apoptotic. While TNF-α mediated TNFR2 activation has a dual role. Several synthetic drugs used as inhibitors of TNF-α for diverse inflammatory diseases possess serious adverse effects, which make patients and researchers turn their focus toward natural medicines, phytochemicals in particular. Phytochemicals targeting TNF-α can significantly improve disease conditions involving TNF-α with fewer side effects. Here, we reviewed known TNF-α inhibitors, as well as lately studied phytochemicals, with a role in inhibiting TNF-α itself, and TNF-α-mediated signaling in inflammatory diseases focusing mainly on CNS disorders.

3,6′-Dithiopomalidomide Ameliorates Hippocampal Neurodegeneration, Microgliosis and Astrogliosis and Improves Cognitive Behaviors in Rats with a Moderate Traumatic Brain Injury

“…Unfortunately, the use of thalidomide in animal disease models and humans has proved difficult to translates as an approach to reduce neuroinflammation accompanying neurodegeneration [ 42 ] consequent to the development of intolerable off-target actions that proved dose-limiting prior to clinically relevant TNF-α lowering anti-inflammatory effects, as evidenced in a recent human Alzheimer’s disease thalidomide clinical trial [ 43 ]. This prompted a recently initiated lenalidomide Alzheimer’s disease clinical trial (MCLENA-1) [ 44 ], as lenalidomide is a more potent second-generation analog against TNF-α within the IMiD drug class [ 45 ]. Additionally, there is well-documented teratogenic sequela with this drug class that, although not potentially relevant for Alzheimer’s patients due to their age, may be relevant for TBI subjects, thereby motivating the search for new compounds that are less encumbered by prohibitive adverse actions [ 32 , 41 , 46 ].…”

Soluble tumor necrosis factor-alpha-induced hyperexcitability contributes to retinal ganglion cell apoptosis by enhancing Nav1.6 in experimental glaucoma

“…Tumor necrosis factor-alpha (TNF-α), a classical inflammation cytokine, exerts multiple functions in the nervous system by binding to two types of TNF-α receptor (TNFR1 and TNFR2) [ 16 , 17 ]. Soluble TNF-α (17 kDa) preferentially binds to TNFR1, leading to neuroinflammation and cell death [ 18 – 20 ], while transmembrane TNF-α (22 kDa) primarily binds to TNFR2 that mediates neuroprotective effects [ 21 , 22 ].…”

Terpenoids from Abies holophylla Attenuate LPS-Induced Neuroinflammation in Microglial Cells by Suppressing the JNK-Related Signaling Pathway

“…Previous studies have indicated that NO and iNOS overproduction increases oxidative stress and is related to various neurodegenerative diseases [ 6 , 21 , 22 ]. Additionally, the release of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) by microglia is increased during neuroinflammation [ 23 , 24 ]. In our study, chloroform- and hexane-soluble fractions of A. holophylla and their active compounds significantly inhibited the LPS-induced ROS and NO production with increased COX-2 and PGE2 expression.…”