Neuroprotective effect of melatonin on soluble Aß1-42-induced cortical neurodegeneration via Reelin-Dab1 signaling pathway.

OBJECTIVE: Soluble Aß1-42 oligomers play a vital role in the development and pathogenesis of Alzheimer's disease (AD). Melatonin could delay the progress of AD through multiple mechanisms. Reelin-Dab1 signaling plays an important role in AD, including neuronal function and synaptic plasticity. However, whether melatonin could exert its neuroprotective function against soluble Aß1-42-induced neurotoxicity during AD development through regulating Reelin-Dab1 signaling remains poorly understood. METHODS: AD rat model was established by soluble Aß1-42 repeated intracerebroventricular injection. Using immunohistochemistry and Western blot analyses, the effect of melatonin on synaptic plasticity, neuritic degeneration, and astrocyte activation was investigated in cerebral cortex. Meanwhile, the expression of Reelin and Dab1 was also examined in cerebral cortex. In our in vitro study, Reelin-Dab1 signaling was inhibited by Reelin antibody, and neuroprotective effect of melatonin against Aß1-42 was further determined. RESULTS: Melatonin ameliorated the neurotoxiciy and astrocyte activation induced by Aß1-42 in the cerebral cortex. Melatonin also blocked the reduction in Reelin and Dab1 expression induced by Aß1-42. Using in vitro study, Reelin inactivation completely abolished the protective effect of melatonin against Aß1-42-induced neurotoxicity. DISCUSSION: Melatonin might play its neuroprotective role against Aß1-42 through mediating Reelin-Dab1 signaling pathway. Melatonin could be a safe and remarkable therapeutic candidate for AD and other aged-associated neurodegenerative diseases.

Role of ß-1,3-galactosyltransferase 2 in trigeminal neuronal sensitization induced by peripheral inflammation.

Glycosyltransferases are enzymes that catalyze the formation of a variety of glycoconjugates. Glycoconjugates play important roles in the nervous system. ß-1,3-Galactosyltransferase 2 (B3galt2) belongs to the family of ß-1,3-galactosyltransferase, which is one of the major types of glycosyltransferases. Dental pulp inflammation may cause neurophysiological alterations in the trigeminal ganglion (TG), and serve as a good model for investigating the peripheral inflammation and trigeminal neuronal sensitization. In the present study, we investigated the expression of B3galt2 in neuroinflammation using the dental pulp inflammatory model induced by lipopolysaccharide in rat. The expression of B3galt2 gene and protein were determined by reverse transcription PCR, immunohistochemistry and western blot analysis. ELISA assays were used to measure the levels of cytokines in the TG neurons. Toll-like receptor 4 (TLR4) and nuclear factor-κB (NFκB) were evaluated by immunohistochemistry and western blotting. Our results demonstrated that B3galt2 was expressed in the TG, and dental pulp inflammation up-regulated B3galt2 expression in the TG. B3galt2 gene knockdown reduced the secretion of TNFα and IL-6 in the TG neurons. The expression of TLR4 and NFκB in the TG was activated during the inflammation, but B3galt2 gene knockdown inhibited the expression of TLR4 and NFκB. These observations indicated that dental pulp inflammation could induce B3galt2 expression in TG, and that B3galt2 might play a regulatory role in TG neuronal sensitization. These findings suggest that B3galt2 may play an important role in trigeminal neuronal sensitization induced by peripheral inflammation via mediating TLR4/NFκB signaling pathway.

Dynamic Regulation of Delta-Opioid Receptor in Rat Trigeminal Ganglion Neurons by Lipopolysaccharide-induced Acute Pulpitis.

INTRODUCTION: Delta-opioid receptor (DOR) and its endogenous ligands distribute in trigeminal system and play a very important role in modulating peripheral inflammatory pain. DOR activation can trigger p44/42 mitogen-activated protein kinase (ERK1/2) and Akt signaling pathways, which participate in anti-inflammatory and neuroprotective effects. In this study, our purpose was to determine the dynamic changes of DOR in trigeminal ganglion (TG) neurons during the process of acute dental pulp inflammation and elucidate its possible mechanism. METHODS: Forty rats were used to generate lipopolysaccharide-induced acute pulpitis animal models at 6, 12, and 24 hours and sham-operated groups. Acute pulpitis was confirmed by hematoxylin-eosin staining, and TG neuron activation was determined by anti-c-Fos immunohistochemistry. DOR protein and gene expression in TG was investigated by immunohistochemistry, Western blotting, and real-time polymerase chain reaction, and DOR expression in trigeminal nerves and dental pulp was also determined by immunohistochemistry. To further investigate the mechanism of DOR modulating acute inflammation, the change of pErk1/2 and pAkt in TG was examined by immunohistochemistry. RESULTS: Lipopolysaccharide could successfully induce acute pulpitis and activated TG neurons. Acute pulpitis could dynamically increase DOR protein and gene expression at 6, 12, and 24 hours in TG, and DOR dimerization was significantly increased at 12 and 24 hours. Acute pulpitis also induced the dynamic change of DOR protein in trigeminal nerve and dental pulp. Furthermore, ERK1/2 and Akt signaling pathways were inhibited in TG after acute pulpitis. CONCLUSIONS: Increased DOR expression and dimerization may play important roles in peripheral acute inflammatory pain.