Neuroscience
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Parkinson's disease (PD) is a chronic and progressive neurological disorder that is characterized by the loss of dopaminergic neurons in the substantia nigra. Dopamine, via the oxidative stress that it generates in the cytosol, could contribute to the selective loss of neurons observed in PD. Protein L-isoaspartyl methyltransferase (PIMT) is an enzyme that repairs L-isoaspartyl-containing proteins and possesses anti-apoptotic properties. ⋯ Conversely, H2O2 inhibited in a dose-dependent manner the transcriptional activity of PCMT1 promoter. Therefore, our findings identified new molecular mechanisms, cytosolic dopamine and its resulting ROS, as inhibitors of PIMT expression. This suggests that ROS generated from cytosolic dopamine could reduce both the PCMT1 gene promoter activity and the PIMT protein level thus decreasing its capacity to repair proteins involved in apoptosis and could contribute to neuronal cell death observed in PD.
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Opiate analgesia in the spinal cord is impaired during neuropathic pain. We hypothesized that this is caused by a decrease in μ-opioid receptor inhibition of neurotransmitter release from primary afferents. To investigate this possibility, we measured substance P release in the spinal dorsal horn as neurokinin 1 receptor (NK1R) internalization in rats with chronic constriction injury (CCI) of the sciatic nerve. ⋯ In contrast, DAMGO still inhibited substance P release after inflammation of the hind paw with complete Freund's adjuvant and in naïve rats. This loss of inhibition was not due to μ-opioid receptor downregulation in primary afferents, because their colocalization with substance P was unchanged, both in dorsal root ganglion neurons and primary afferent fibers in the dorsal horn. In conclusion, nerve injury eliminates the inhibition of substance P release by μ-opioid receptors, probably by hindering their signaling mechanisms.
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We have examined the functional expression of Toll-like receptor 4 (TLR4) in adult male rat dorsal root ganglion (DRG) cells in culture by studying changes in pro-inflammatory cytokines and cyclooxygenase (COX)-dependent prostanoid production. In the mixed population of DRG neurons and glial cells, only DRG neurons expressed cell surface TLR4 along with MD-2 and CD14. This classical TLR4 signaling complex on DRG neurons responded to lipopolysaccharide (LPS) with a TLR4-dependent and time-dependent increase in interleukin-1β and tumor necrosis factor-α mRNA expression which was entirely dependent on NF-κB activity. ⋯ LPS surprisingly produced a time-dependent decrease in COX-1 protein which likely facilitates the COX-2-dependent production of prostaglandin E2 and prostacyclin. Our study is the first to demonstrate the activation of TLR4-dependent production of prostaglandin E2 and prostacyclin in DRG cell cultures. Our findings support the concept that the activation of TLR4 on primary sensory neurons by endogenous ligands may underlie neuropathic and inflammatory pain states.
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Though sex differences in pain and analgesia are known, underlying mechanisms remain elusive. This study addresses the selective contribution of membrane estrogen receptors (mERs) and mER-initiated non-genomic signaling mechanisms in our previously reported estrogen-induced attenuation of α2-adrenoceptor-mediated antinociception. By selectively targeting spinal mERs in ovariectomized female rats using β-estradiol 6-(O-carboxy-methyl)oxime bovine serum albumin (E2BSA) (membrane impermeant estradiol analog), and ERα selective agonist 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), ERβ selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), G-protein-coupled estrogen receptor 30 (GPR30) agonist G1 and Gq-coupled mER (Gq-mER) agonist STX, we provide strong evidence that Gq-mER activation may solely contribute to suppressing clonidine (an α2-adrenoceptor agonist)-induced antinociception, using the nociceptive tail-flick test. ⋯ Immunoblotting of spinal tissue revealed that mER activation increased levels of phosphorylated extracellular signal-regulated kinase (ERK) but not of protein kinase A (PKA) or C (PKC). In vivo inhibition of ERK with U0126 blocked the effect of STX and restored clonidine antinociception. Although estrogen-induced delayed genomic mechanisms may still exist, data presented here indicate that Gq-mER may solely mediate estradiol-induced attenuation of clonidine antinociception via a rapid, reversible, and ERK-dependent, non-genomic mechanism, suggesting that Gq-mER blockade might provide improved analgesia in females.
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Homer protein, a member of the post-synaptic density protein family, plays an important role in the neuronal synaptic activity and is extensively involved in neurological disorders. The present study investigates the role of Homer1b/c in modulating neuronal survival by using an in vitro traumatic neuronal injury model, which was achieved by using a punch device that consisted of 28 stainless steel blades joined together and produced 28 parallel cuts. ⋯ Therefore, Homer1b/c not only modulated the mGluR1a-inositol 1,4,5-triphosphate receptors-Ca(2+) signal transduction pathway, but also regulated the expression of mGluR1a in mechanical neuronal injury. These findings indicate that the suppression of Homer1b/c expression potentially protects neurons from glutamate excitotoxicity after injury and might be an effective intervention target in traumatic brain injury.