Neuroscience
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The endogenous tetrapeptide endomorphin-2 (EM2) participates in pain modulation by binding to pre- and/or post-synaptic μ opioid receptor (MOR). In the present study, pathological expression and antinociceptive effects of EM2 at the spinal level were investigated in a rat model of bone cancer pain. The model was established by introducing Walker 256 mammary gland carcinoma cells into the tibia medullary cavity. ⋯ Furthermore, topical application of EM2 dose-dependently inhibited the electrically evoked C-fiber responses and postdischarge of wide dynamic range (WDR) neurons within the spinal cord (p < 0.05), and pretreatment with β-FNA abolished the hyperactivity of these neurons. Compared with the antinociception of morphine which took effect from 40 min to 100 min post application, the analgesic action of EM2 was characterized by quick onset and short-lived efficacy (p < 0.05), being most potent at 10 min and lasting about 20 min. These findings indicate that the down-regulated spinal EM2 is an important contributor to the neuropathological process of bone cancer pain and enhancing activation of EM2/μ receptor signaling might provide a therapeutic alternative to optimizing the treatment of cancer-induced bone pain.
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Up-regulation in phosphodiesterase 1 (PDE1) expression and decreased levels of cyclic nucleotides (cAMP and cGMP) have been reported in patients and experimental animal models of Parkinson's disease (PD). Phosphodiesterase (PDE) inhibitors have been reported to be beneficial in cognitive and motor deficit states. The present study is designed to investigate the effect of vinpocetine, a PDE1 inhibitor in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental PD-like symptoms in rats. ⋯ Chronic administration of vinpocetine (for 14 days) significantly and dose dependently attenuated movement disabilities and oxidative-nitrosative stress in MPTP-treated rats. Moreover, vinpocetine treatment enhances cyclic nucleotide levels and restores the dopamine level in MPTP-treated rats. The observed results of the present study are indicative of the therapeutic potential of vinpocetine in PD.
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Mice lacking the homeodomain transcription factor Engrailed-2 (En2(-/-) mice) are a well-characterized model for autism spectrum disorders (ASD). En2(-/-) mice present molecular, neuropathological and behavioral deficits related to ASD, including down-regulation of ASD-associated genes, cerebellar hypoplasia, interneuron loss, enhanced seizure susceptibility, decreased sociability and impaired cognition. Specifically, impaired spatial learning in the Morris water maze (MWM) is associated with reduced expression of neurofibromin and increased phosphorylation of extracellular-regulated kinase (ERK) in the hippocampus of En2(-/-) adult mice. ⋯ Here we show that SynI mRNA and protein levels are down-regulated in the hippocampus of naïve and MWM-treated En2(-/-) mice, as compared to WT controls. This down-regulation is paralleled by reduced levels of SynI phosphorylation at Ser549 and Ser553 residues in the hilus of mutant mice, before and after MWM. These data indicate that in En2(-/-) hippocampus, neurofibromin-dependent pathways converging on SynI phosphorylation might underlie hippocampal-dependent learning deficits observed in En2(-/-) mice.