Neuroscience
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Comparative Study
Low-threshold heat receptor in chick sensory neurons is upregulated independently of nerve growth factor after nerve injury.
In mammals, the cloned low-threshold heat receptor, vanilloid receptor subtype 1 (VR1), is involved in the genesis of thermal hyperalgesia after inflammation. However, there is evidence that VR1 is not involved in the thermal hyperalgesia that occurs after nerve injury. In search for other heat receptors which might be involved in this phenomenon, we previously demonstrated that chick dorsal root ganglion neurons, which are insensitive to capsaicin, respond to low-threshold heat. ⋯ On the molecular level, there was an increase of chick VR1 mRNA level in dorsal root ganglion cells cultured for 3 days in medium lacking NGF. In rat dorsal root ganglion neurons cultured for 1-4 days without NGF, patch-clamp experiments revealed that after 1 day almost all neurons responding to heat also responded to capsaicin, whereas after 3-4 days, more than one-half of the heat-responsive neurons did not respond to capsaicin. These data suggest the existence of low-threshold heat receptors in chick dorsal root ganglion neurons, the expression of which is regulated independently of NGF.
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Comparative Study
Relationship between capsaicin-evoked substance P release and neurokinin 1 receptor internalization in the rat spinal cord.
The relationship between substance P release and the activation of its receptor in the spinal cord remains unclear. Substance P release is usually measured by radioimmunoassay, whereas the internalization of the neurokinin 1 (NK1) receptor has been used to assess its activation by noxious stimuli. Our objective was to compare substance P release and NK1 receptor internalization produced by capsaicin in rat spinal cord slices. ⋯ The correlation was good for laminae I (R(2)=0.82) and III (R(2)=0.78), but it was poor (R(2)=0.35) for lamina IV because NK1 receptor internalization kept on increasing at high concentrations of capsaicin, whereas substance P release decreased. In conclusion, amounts of substance P able to activate NK1 receptors may fall under the threshold of detection of radioimmunoassay. Conversely, radioimmunoassay often detects levels of substance P release well over those required to saturate NK1 receptors in the superficial dorsal horn, but that may be able to activate these receptors in nearby regions of the spinal cord.
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A novel calmodulin (CaM) antagonist DY-9760e, (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate), with an apparent neuroprotective effect in vivo, potently inhibits CaM-dependent nitric oxide synthase in situ. In the present study, we determined whether DY-9760e inhibits nitric oxide (NO) production and protein nitration by peroxynitrite (ONOO(-)) formation in the hippocampal CA1 region of gerbils after transient forebrain ischemia. In freely moving gerbils, NO production after 10-minute forebrain ischemia was monitored consecutively with in vivo brain microdialysis. ⋯ Western blot and immunohistochemical analyses using an anti-nitrotyrosine antibody as a marker of ONOO(-) formation indicated a marked increase in nitrotyrosine immunoreactivity in the pyramidal neurons of the CA1 region 2 h after reperfusion, and DY-9760e significantly inhibited increased nitrotyrosine immunoreactivity. Coincident with the inhibition of the NO production and protein tyrosine nitration, pretreatment with DY-9760e rescued the delayed neuronal death in the hippocampal CA1 region. These results suggest that the inhibitory effects of DY-9760e on the NO-ONOO(-) pathway partly account for its neuroprotective effects in cerebral ischemia.
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Comparative Study
The mitochondrial complex I inhibitor annonacin is toxic to mesencephalic dopaminergic neurons by impairment of energy metabolism.
The death of dopaminergic neurons induced by systemic administration of mitochondrial respiratory chain complex I inhibitors such as 1-methyl-4-phenylpyridinium (MPP(+); given as the prodrug 1-methyl-1,2,3,6-tetrahydropyridine) or the pesticide rotenone have raised the question as to whether this family of compounds are the cause of some forms of Parkinsonism. We have examined the neurotoxic potential of another complex I inhibitor, annonacin, the major acetogenin of Annona muricata (soursop), a tropical plant suspected to be the cause of an atypical form of Parkinson disease in the French West Indies (Guadeloupe). When added to mesencephalic cultures for 24 h, annonacin was much more potent than MPP(+) (effective concentration [EC(50)]=0.018 versus 1.9 microM) and as effective as rotenone (EC(50)=0.034 microM) in killing dopaminergic neurons. ⋯ Attempts to restore oxidative phosphorylation with lactate or pyruvate failed to provide protection to dopaminergic neurons whereas idoacetate, an inhibitor of glycolysis, inhibited the survival promoting effects of glucose and mannose indicating that these two hexoses acted independently of mitochondria by stimulating glycolysis. In conclusion, our study demonstrates that annonacin promotes dopaminergic neuronal death by impairment of energy production. It also underlines the need to address its possible role in the etiology of some atypical forms of Parkinsonism in Guadeloupe.
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Numerous studies have investigated the expression of various cytokine families in the CNS after brain injury. The gp130 or interleukin (IL)-6-type cytokines have received a great deal of focus, and it is clear that they exhibit an acute and robust upregulation in various brain injury models. We are interested to determine, however, whether endogenously expressed cytokines in the CNS act in a direct neuromodulatory manner. ⋯ SOCS-2 displayed a relatively higher level of basal expression, particularly in CA3, and a mild and transient downregulation by 24 h. These findings corroborate the hypothesis that seizure-induced gp130 cytokines play a direct neuromodulatory role in the hippocampus. Since in our previous study we did not detect cytokine receptor expression in non-principal cells, it is unclear what elicits SOCS-3 expression in this population.