ObjectiveTo investigate the inhibitory effect of tauroursodeoxycholic acid （TUDCA） on neurogenic heterotopic ossification （NHO） after spinal cord injury and its potential mechanism. MethodsSPF-grade male C57BL/6 mice were used to establish an NHO model. The mice were randomly divided into three groups： sham operation group （laminectomy only）， NHO model group （spinal cord injury + intramuscular injection of cardiotoxin）， and TUDCA treatment group （NHO model + daily intragastric administration of TUDCA at 200 mg/kg for 4 consecutive weeks）. The area and maturity of heterotopic ossification were quantitatively assessed by micro-computed tomography（micro-CT） and hematoxylin-eosin（H&E） staining. Flow cytometry was used to quantify the interleukin（IL）-1β secretion level of M2 macrophages. RAW264.7 macrophages were cultured in vitro and divided into control， tumor necrosis factor（TNF）α， and TNFα+TUDCA （200 μmol/L） groups to detect the expression level of the polarization marker CD206. Additionally， macrophages were divided into control， TUDCA 200 μmol/L， and TUDCA 400 μmol/L groups to assess the IL-1β secretion level. ResultsCompared with the NHO group， the bone volume in the TUDCA-treated group was significantly reduced （12.69±1.13 vs. 7.647±1.19， P=0.003）. Compared with the TNFα group， qPCR results showed that the expression of the M2 macrophage marker CD206 was significantly upregulated in the TNFα+TUDCA group （0.55±0.019，1.11±0.023， P＜0.001）. Compared with the control group， ELISA results showed that TUDCA stimulation of macrophages significantly upregulated IL-1β secretion （404.7±24.38 vs. 652.8±32.61， P=0.003 7）. TUDCA administration upregulated IL-1β secretion by local muscle macrophages and inhibited heterotopic ossification formation. ConclusionsTUDCA might participate in inhibiting NHO formation by inducing M2 macrophage polarization and upregulating IL-1β secretion， thereby alleviating the development and progression of neurogenic heterotopic ossification after spinal cord injury. This finding provides experimental evidence for expanding the application of TUDCA in the treatment of complications following spinal cord injury.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. A cardinal histopathologic feature of HD is the progressive loss of striatal medium spiny neurons. As there is no effective treatment for this fatal disease so far, we explore the therapeutic potential of nortriptyline to identify drugs that might be effective treatments for HD. N548mu [ 1955-128] huntingtin stable ST14A cell line was cultured and incubated in the presence or absence of serial concentrations of nortriptyline. Then R6/2 transgenic HD mice were treated with nortriptyline from five to twenty-one weeks of age. Nortriptyline protected striatal cells expressing mutant huntingtin when shifted to a nonpermissive temperature. Nortriptyline delay the disease onset to 127 d in R6/2 mice as compared with 102 d in saline-treated controls, but nortriptyline did not significantly delay mortality. As a gross marker of lack of systemic toxicity, there was no significant difference in the weight of the treated and control R6/2 mice. The results demonstrate that clinically reasonable doses of one of the identified drugs, nortriptyline, delays disease onset in a mouse model of the disease more than any previously identified compound. The most desirable features of a drug for HD are minimal toxicity and the ability to extend symptom-free living. Nortriptyline appears to be one such good candidate.