Background and Purpose New remedies are required for the treatment of neuropathic pain due to insufficient efficacy of available therapies. This study provides a novel approach to develop painkillers for chronic pain treatment. Experimental Approach The rat formalin pain test and spinal nerve ligation model of neuropathic pain were used to evaluate antinociception of protopanaxadiol. Primary cell cultures, immunofluorescence staining, and gene and protein expression were also performed for mechanism studies. Key Results Gavage protopanaxadiol remarkably produces pain antihypersensitive effects in neuropathic pain, bone cancer pain and inflammatory pain, with efficacy comparable with gabapentin. Long‐term PPD administration does not induce antihypersensitive tolerance, but prevents and reverses the development and expression of morphine analgesic tolerance. Oral protopanaxadiol specifically stimulates spinal expression of dynorphin A in microglia but not in astrocytes or neurons. Protopanaxadiol gavage‐related pain antihypersensitivity is abolished by the intrathecal pretreatment with the microglial metabolic inhibitor minocycline, dynorphin antiserum or specific κ‐opioid receptor antagonist GNTI. Intrathecal pretreatment with glucocorticoid receptor)antagonists RU486 and dexamethasone‐21‐mesylate, but not GPR‐30 antagonist G15 or mineralocorticoid receptor antagonist eplerenone, completely attenuates protopanaxadiol‐induced spinal dynorphin A expression and pain antihypersensitivity in neuropathic pain. Treatment with protopanaxadiol, the glucocorticoid receptor agonist dexamethasone and membrane‐impermeable glucocorticoid receptor agonist dexamethasone‐BSA in cultured microglia induces remarkable dynorphin A expression, which is totally blocked by pretreatment with dexamthasone‐21‐mesylate. Conclusion and Implications All the results, for the first time, indicate that protopanaxadiol produces pain antihypersensitivity in neuropathic pain probably through spinal microglial dynorphin A expression after glucocorticoid receptor activation and hypothesize that microglial membrane glucocorticoid receptor/dynorphin A pathway is a potential target to discover and develop novel painkillers in chronic pain.
Abstract Loss of retinal ganglion cells (RGCs) is the final common end point for many optic neuropathies, ultimately leading to irreversible vision loss. Endogenous RGC regeneration from Müller cells presents a promising approach to treat these diseases, but mammalian retinas lack regenerative capacity. Here, we report a small molecule cocktail that causes endogenous Müller cell proliferation, migration, and specification to newly generated chemically induced RGCs (CiRGCs) in NMDA injured mice retina. Notably, regenerated CiRGCs extend axons towards optic nerve, and rescue vision post-NMDA treatment. Moreover, we successfully reprogrammed human primary Müller glia and fibroblasts into CiRGCs using this chemical-only approach, as evidenced by RGC-specific gene expression and chromatin signature. Additionally, we show that interaction between SOX4 and NF-kB determine CiRGC fate from Müller cells. We anticipate endogenous CiRGCs would have therapeutic potential in rescuing vision for optic nerve diseases.
Molybdenum importance for appropriate plant functioning and growth is inconsistent by the most of the plants in respect to the total quantity that is obligatory for them.
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