MATERIALS AND METHODS: After searching the records for a 15-year period at the London Health Sciences Centre Pathology Department, we identified 8 cases of surgical acute lesion biopsies in which clinical MS diagnoses were made before or after the biopsy.
RESULTS: The white matter pathologies in these cases could be sorted into 3 morphological patterns. The first pattern, which represents typical demyelinated plaques, was observed in 4 cases and was characterised by nearly complete demyelination accompanied by variable degrees of axon preservation and axonal swelling. The second pattern was observed in 3 cases and was characterised by demyelinating lesions containing variable numbers of myelinated axons mixed with a few demyelinated axons and variable numbers of axonal swellings. The myelinated axons ranged from scattered fibres to bands of variable thickness, and the demyelination was a mixture of primary and secondary demyelination. The third pattern was observed in 1 case and was characterised by well-demarcated areas of reduced myelin staining and numerous apoptotic nuclei. Axonal staining revealed many fragmented axons with reduced myelin staining but no definitely demyelinated axons.
CONCLUSIONS: This report shows that the predominant pathology underlying acute MS-related lesions is not limited to demyelination but can include axonal degeneration alone or in combination with primary demyelination which reflect different pathogenesis for these acute lesions.
METHODS: We employed the HDAC inhibitor (HDACi) sodium phenylbutyrate (PBA) to address this question in an in vitro RT4 SC inflammation model and an in vivo sciatic nerve transection injury model to examine the effects of HDAC inhibition on the expression of pro-inflammatory cytokines. Furthermore, we assessed the outcomes of suppression of extended inflammation on the regenerative potential of nerves by assessing axonal regeneration, remyelination, and reinnervation.
RESULTS: Significant reductions in lipopolysaccharide (LPS)-induced pro-inflammatory cytokine (tumor necrosis factor-α [TNFα]) expression and secretion were observed in vitro following PBA treatment. PBA treatment also affected the transient changes in nuclear factor κB (NFκB)-p65 phosphorylation and translocation in response to LPS induction in RT4 SCs. Similarly, PBA mediated long-term suppressive effects on HDAC3 expression and activity. PBA administration resulted in marked inhibition of pro-inflammatory cytokine secretion at the site of transection injury when compared with that in the hydrogel control group at 6-week post-injury. A conducive microenvironment for axonal regrowth and remyelination was generated by increasing expression levels of protein gene product 9.5 (PGP9.5) and myelin basic protein (MBP) in regenerating nerve tissues. PBA administration increased the relative gastrocnemius muscle weight percentage and maintained the intactness of muscle bundles when compared with those in the hydrogel control group.
CONCLUSIONS: Suppressing the lengthened state of inflammation using PBA treatment favors axonal regrowth and remyelination following nerve transection injury. PBA treatment also regulates pro-inflammatory cytokine expression by inhibiting the transcriptional activation of NFκB-p65 and HDAC3 in SCs in vitro.
METHODS: Nerve conduit was developed using decellularised artery seeded with C. asiatica-neurodifferentiated MSCs (ndMSCs). A 1.5 cm sciatic nerve injury in Sprague-Dawley rat was bridged with reversed autograft (RA) (n = 3, the gold standard treatment), MSC-seeded conduit (MC) (n = 4) or ndMSC-seeded conduit (NC) (n = 4). Pinch test and nerve conduction study were performed every 2 weeks for a total of 12 weeks. At the 12th week, the conduits were examined by histology and transmission electron microscopy.
RESULTS: NC implantation improved the rats' sensory sensitivity in a similar manner to RA. At the 12th week, nerve conduction velocity was the highest in NC compared with that of RA and MC. Axonal regeneration was enhanced in NC and RA as shown by the expression of myelin basic protein (MBP). The average number of myelinated axons was significantly higher in NC than in MC but significantly lower than in RA. The myelin sheath thickness was higher in NC than in MC but lower than in RA.
CONCLUSION: NC showed promising effects on nerve regeneration and functional restoration similar to those of RA. These findings revealed the neuroregenerative properties of C. asiatica and its potential as an alternative strategy for the treatment of critical size nerve defect.