Chronic pain is among the most prevalent
burdensome disorders worldwide.
The N-methyl-d-aspartate (NMDA) receptor
system plays a critical role in central sensitization, a primary feature
of chronic pain. Despite the proven efficacy of exogenous ligands
to this receptor system in preclinical studies, evidence for the clinical
efficacy of NMDA antagonists for the treatment of chronic pain is
weak. Researchers are studying alternate approaches, rather than direct
inhibition of the NMDA receptors in pain processing neurons. This
indirect approach utilizes the modulation of molecular switches that
regulates the synthesis, maturation, and transport of receptors from
cellular organelles to the synaptic membrane. Kinesins are nanomotors
that anterogradely transport the cargo using microtubule tracks across
the neurons. Various members of the kinesin family, including KIF17,
KIF11, KIF5b, and KIF21a, regulate the intracellular transport of
NMDA receptors. Pharmacological targeting of these ATP-driven nanomotors
could be a useful tool for manipulating the NMDAR functioning. It
could provide the potential for the development of a novel strategy
for the management of chronic pain.
Alcohol consumption for a longer period of time is linked with neuronal damage and an increase in in ammatory signaling resulting in cell death and dementia. Natural compounds are the focus of research due to their high e cacy and good safety pro le. Here we have investigated the effect of chronic epigallocatechin-3-gallate (EGCG) administration against the alcohol-induced cognitive de cit rats. Male Wistar rats were exposed to the ethanol (10 g/kg; oral gavage) for ten weeks and treated with EGCG (25, 50, and 100 mg/kg) for the same duration. Ethanol exposure led to the impaired spatial memory and learning in rats assessed using the Morris water maze and elevated plus-maze test. Further, we assessed the role of EGCG in mitigating the oxidative stress, neuroin ammatory and cell death signaling associated markers. Co-administration with EGCG signi cantly prevented all the behavioral, biochemical and molecular alterations in the different brain regions of ethanol-treated rats in a dose-dependent manner. EGCG suppressed the acetylcholinesterase activity, increased oxidative-nitrosative stress, cytokines (TNF-alpha and IL-1beta), NF-kappa β and caspase-3 levels in both the cortex and hippocampus of ethanol-treated rats. Our preliminary study demonstrated that EGCG improves the oxidonitrosative stress, in ammation, and cell death signaling associated with ethanol-induced cognitive dysfunction. This suggests the potential role of EGCG in mitigating the cognitive de cits associated with chronic alcohol consumption.
Bone cancer pain (BCP) is a distinct pain state showing characteristics of both neuropathic and inflammatory pain. On average, almost 46% of cancer patients exhibit BCP with numbers flaring up to as high as 76% for terminally ill patients. Patients suffering from BCP experience a compromised quality of life, and the unavailability of effective therapeutics makes this a more devastating condition. In every individual cancer patient, the pain is driven by different mechanisms at different sites. The mechanisms behind the manifestation of BCP are very complex and poorly understood, which creates a substantial barrier to drug development. Nevertheless, some of the key mechanisms involved have been identified and are being explored further to develop targeted molecules. Developing a multitarget approach might be beneficial in this case as the underlying mechanism is not fixed and usually a number of these pathways are simultaneously dysregulated. In this review, we have discussed the role of recently identified novel modulators and mechanisms involved in the development of BCP. They include ion channels and receptors involved in sensing alteration of temperature and acidic microenvironment, immune system activation, sodium channels, endothelins, proteaseactivated receptors, neurotrophins, motor proteins mediated trafficking of glutamate receptor, and some bone-specific mechanisms. Apart from this, we have also discussed some of the novel approaches under preclinical and clinical development for the treatment of bone cancer pain.
Alcohol consumption for a longer period of time is linked with neuronal damage and an increase in inflammatory signaling resulting in cell death and dementia. Natural compounds are the focus of research due to their high efficacy and good safety profile. Here we have investigated the effect of chronic epigallocatechin-3-gallate (EGCG) administration against the alcohol-induced cognitive deficit rats. Male Wistar rats were exposed to the ethanol (10 g/kg; oral gavage) for ten weeks and treated with EGCG (25, 50, and 100 mg/kg) for the same duration. Ethanol exposure led to the impaired spatial memory and learning in rats assessed using the Morris water maze and elevated plus-maze test. Further, we assessed the role of EGCG in mitigating the oxidative stress, neuroinflammatory and cell death signaling associated markers. Co-administration with EGCG significantly prevented all the behavioral, biochemical and molecular alterations in the different brain regions of ethanol-treated rats in a dose-dependent manner. EGCG suppressed the acetylcholinesterase activity, increased oxidative–nitrosative stress, cytokines (TNF-alpha and IL-1beta), NF-kappa β and caspase-3 levels in both the cortex and hippocampus of ethanol-treated rats. Our preliminary study demonstrated that EGCG improves the oxido-nitrosative stress, inflammation, and cell death signaling associated with ethanol-induced cognitive dysfunction. This suggests the potential role of EGCG in mitigating the cognitive deficits associated with chronic alcohol consumption.
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