Immunopathological Effects Of Aquaporin-4 Ig G In Neuromyelitis Optica Spectrum Disorders

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Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury

After spinal cord injury, enzymatic digestion of chondroitin sulfate proteoglycans promotes axonal regeneration of central nervous system neurons across the lesion scar. We examined whether chondroitinase ABC (ChABC) promotes the axonal regeneration of rubrospinal tract (RST) neurons following injury to the spinal cord. The effect of a GSK-3β inhibitor, lithium chloride (LiCl), on the regeneration of axotomized RST neurons was also assessed. Adult rats received a unilateral hemisection at the seventh cervical spinal cord segment (C7). Four weeks after different treatments, regeneration of RST axons across the lesion scar was examined by injection of Fluoro-Gold at spinal segment T2, and locomotor recovery was studied by a test of forelimb usage. Injured RST axons did not regenerate spontaneously after spinal cord injury, and intraperitoneal injection of LiCl alone did not promote the regeneration of RST axons. Administration of ChABC at the lesion site enhanced the regeneration of RST axons by 20%. Combined treatment of LiCl together with ChABC significantly increased the regeneration of RST axons to 42%. Animals receiving combined treatment used both forelimbs together more often than animals that received sham or single treatment. Immunoblotting and immunohistochemical analysis revealed that LiCl induced the expression of inactive GSK-3β as well as the upregulation of Bcl-2 in injured RST neurons. These results indicate that in vivo, LiCl inhibits GSK-3β and reinforces the regeneration-promoting function of ChABC through a Bcl-2-dependent mechanism. Combined use of LiCl together with ChABC could be a novel treatment for spinal cord injury.published_or_final_versio

Early release of mitochondrial cytochrome c and the subsequent activation of caspase-3 are involved in the apoptotic death of neonatal motoneurons after injury

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S-allylmercaptocysteine reduces carbon tetrachloride-induced hepatic oxidative stress and necroinflammation via nuclear factor kappa B-dependent pathways in mice

Purpose To study the protective effects and underlying molecular mechanisms of SAMC on carbon tetrachloride (CCl4)-induced acute hepatotoxicity in the mouse model. Methods Mice were intraperitoneally injected with CCl4 (50 μl/kg; single dose) to induce acute hepatotoxicity with or without a 2-h pre-treatment of SAMC intraperitoneal injection (200 mg/kg; single dose). After 8 h, the blood serum and liver samples of mice were collected and subjected to measurements of histological and molecular parameters of hepatotoxicity. Results SAMC reduced CCl4-triggered cellular necrosis and inflammation in the liver under histological analysis. Since co-treatment of SAMC and CCl4 enhanced the expressions of antioxidant enzymes, reduced the nitric oxide (NO)-dependent oxidative stress, and inhibited lipid peroxidation induced by CCl4. SAMC played an essential antioxidative role during CCl4-induced hepatotoxicity. Administration of SAMC also ameliorated hepatic inflammation induced by CCl4 via inhibiting the activity of NF-κB subunits p50 and p65, thus reducing the expressions of pro-inflammatory cytokines, mediators, and chemokines, as well as promoting pro-regenerative factors at both transcriptional and translational levels. Conclusions Our results indicate that SAMC mitigates cellular damage, oxidative stress, and inflammation in CCl4-induced acute hepatotoxicity mouse model through regulation of NF-κB. Garlic or garlic derivatives may therefore be a potential food supplement in the prevention of liver damage

Lithium Suppresses Astrogliogenesis by Neural Stem and Progenitor Cells by Inhibiting STAT3 Pathway Independently of Glycogen Synthase Kinase 3 Beta

Transplanted neural stem and progenitor cells (NSCs) produce mostly astrocytes in injured spinal cords. Lithium stimulates neurogenesis by inhibiting GSK3b (glycogen synthetase kinase 3-beta) and increasing WNT/beta catenin. Lithium suppresses astrogliogenesis but the mechanisms were unclear. We cultured NSCs from subventricular zone of neonatal rats and showed that lithium reduced NSC production of astrocytes as well as proliferation of glia restricted progenitor (GRP) cells. Lithium strongly inhibited STAT3 (signal transducer and activator of transcription 3) activation, a messenger system known to promote astrogliogenesis and cancer. Lithium abolished STAT3 activation and astrogliogenesis induced by a STAT3 agonist AICAR (5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside), suggesting that lithium suppresses astrogliogenesis by inhibiting STAT3. GSK3β inhibition either by a specific GSK3β inhibitor SB216763 or overexpression of GID5-6 (GSK3β Interaction Domain aa380 to 404) did not suppress astrogliogenesis and GRP proliferation. GSK3β inhibition also did not suppress STAT3 activation. Together, these results indicate that lithium inhibits astrogliogenesis through non-GSK3β-mediated inhibition of STAT. Lithium may increase efficacy of NSC transplants by increasing neurogenesis and reducing astrogliogenesis. Our results also may explain the strong safety record of lithium treatment of manic depression. Millions of people take high-dose (>1 gram/day) lithium carbonate for a lifetime. GSK3b inhibition increases WNT/beta catenin, associated with colon and other cancers. STAT3 inhibition may reduce risk for cancer

Lithium chloride and chondroitinase ABC promote axonal regeneration of rubrospinal neurons after spinal cord injury

Axons in the spinal cord fail to regenerate spontaneously after injury. We examined whether chondroitinase ABC (ChABC) promote the axonal regeneration of rubrospinal tract (RST) neurons following injury of the spinal cord. We also assessed the effect of lithium chloride (LiCl) on the regeneration of RST neurons in the injured spinal cord. Adult female Sprague–Dawley rats were used in this study. Under anesthesia with ketamine and xylazine, the animals received a unilateral hemisection at the seventh cervical spinal cord segment (C7). Four weeks after the injury, regeneration of RST axons across the lesion scar was examined by injection of Fluoro-Gold at spinal segment T2. The recovery of motor function was studied on a test of forelimb usage. RST neurons did not regenerate their axons after spinal cord injury. Intraperitoneal injection of LiCl alone did not promote the axonal regeneration of RST neurons. Administration of ChABC at the lesion site promoted the regeneration of RST axons by 20%. Combined treatment of LiCl together with ChABC significantly increased the regeneration of RST axons to 42%. Animals receiving the combined treatment used both forelimbs together more often than animals received sham or single treatment. Immunoblotting and immunohistochemical analysis revealed that administration of LiCl induced the expression of inactive GSK-3 and the upregulation of Bcl-2 in RST neurons after spinal cord injury. These results suggest that LiCl inhibits GSK-3 and reinforces the regeneration-promoting effect of ChABC through a Bcl-2 dependent mechanism. Combined use of LiCl together with ChABC could be a potential treatment for spinal cord injury. Acknowledgment: This study was supported by the University of Hong Kong

Enhanced gene transfer into skeletal muscle by electroporation in neonatal mice

Presentation no. 881.13Local delivery of electric pulses is an efficient technology for muscle transfection with foreign gene in vivo. We examined the efficiency of naked DNA transfer into skeletal muscle by in vivo electroporation in neonates. We used pCMV-EGFP as the expression vector. Ten μg of plasmid DNA were injected into the biceps of neonatal 7-day-old C57BL/6 mice. Immediately after the injection, electric pulses were delivered with a square wave electroporator transcutaneously. Ten pulses were delivered and the duration of the each pulse was 500 ms, with 500 ms interpulse delay. Various values of voltage were tested. One day after the operation, the muscle fibers did not express EGFP neither in the electroporated nor nonelectroporated groups. Application of electric pulses with 50V increased the number of EGFP expressing muscle fibers by 68 folds 3 days after the operation, in comparison with non-electroporated muscle. The enhancement of EGFP expression declined to 49 and 42 folds 7 and 14 days, respectively, following the operation. Twenty-eight days after operation, there were only few EGFP expressing muscle fibers in the electroporated group, whereas no EGFP positive fibers were observed in the nonelectroporated group. Delivery of electric pulses at either 10V or 900V was significantly less efficient in enhancing the expression of EGFP in neonatal muscle fibers. Our results indicate that significant enhancement of foreign gene expression in vivo can be achieved in neonatal muscles. This is crucial for the development of gene therapy and the developmental studies of spinomuscular neurodegenerative diseases. Supported by a grant from Hong Kong Research Grants Council HKU7254/98M & HKU7024/99

Additive effect of NOS inhibitor and neurotrophic factors on the survival of injured Clarke's neurons

The present study examined the effect of treatment with the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) together with peripheral nerve (PN) graft or brain-derived neurotrophic factor (BDNF) on the survival of CN neurons at the L1 level of the spinal cord following hemisection at T11. In control animals 41% of CN neurons survived 15 days after the hemisection, and 48% of these expressed NOS. Treatment with either PN graft implantation or continuous infusion of BDNF increased the survival rate of CN neurons to 70%; 70% of these expressed NOS. Combined L.-NAME and PN graft or L-NAME and BDNF improved the rescue rate up to 94%, but only 33% expressed NOS. Our results suggest that the expression of NOS, might adversely influence the neuroprotective function of neurotrophic factors on injured CN neurons in the spinal cord.link_to_subscribed_fulltex