Spinal Cord Injury Induced Arrest in Estrous Cycle of Rats is Ameliorated by S-nitrosoglutathione: Novel Therapeutic Agent to Treat Amenorrhea

Abstract

Introduction Amenorrhea following spinal cord injury (SCI) has been well documented. There has been little research on the underlying molecular mechanisms and therapeutics. Aim The purpose of the present study was to investigate the effect of GSNO in ameliorating SCI-induced amenorrhea through affecting the expression of CX43, NFkB, and ERβ protein. Methods SCI was induced in female SD rats at the T9-T10 level. Estrous stage was determined by vaginal smear. GSNO (50 μg/kg body weight) was gavage fed daily. Animals were sacrificed on day 7 and 14 post SCI. Ovaries were fixed for histological and biochemical studies. Expression levels of ERβ, CX-43, and NFkB were analyzed by Western blot and immunofluorescence. Main Outcome Measures GSNO hastens resumption of the estrous cycle following SCI-induced transient arrest. Results Resumption of estrous cycle was hastened by GSNO. Atretic and degenerating follicles seen in the ovary of SCI rats on day 14 post-SCI were decreased in GSNO treated animals. The increased CX43 expression observed with SCI ovary was decreased by GSNO. ERβ expression decreased significantly on day 7 and 14 post-SCI and was restored with GSNO treatment. Following SCI, NFkB expression was increased in the ovarian follicles and the expression was reduced with GSNO administration. The number of terminal deoxynucleotidyl transferase-mediated biotinylated uridine triphosphate (UTP) nick end labeling positive follicular and luteal cells was increased after SCI. GSNO-treated animals had significantly fewer apoptotic cells in the ovary. Conclusion SCI-induced amenorrhea is accompanied by an increase in CX43 expression and a decrease in ERβ expression. SCI animals treated with GSNO resumed the estrous cycle significantly earlier. These results indicate a potential therapeutic value for GSNO in treating amenorrhea among SCI patients.

S-nitrosoglutathione reduces tau hyper-phosphorylation and provides neuroprotection in rat model of chronic cerebral hypoperfusion

“…In this study, we observed that systemic GSNO treatment attenuated the tau hyperphosphorylation and neurodegeneration in rat model of pBCCAO. Similar to studies with other CNS disease animal models (Khan et al, 2005; Khan et al, 2011; Khan et al, 2015; Shunmugavel et al, 2012). These observations indicate that GSNO-induced neuroprotection could be a consequence of its activities on cerebrovascular functions as well as direct contribution of GSNO-mediated signaling pathways for neurodegeneration.…”

“…Moreover, it has a significant anti-platelet activity (de Belder et al, 1994) and was used therapeutically as a platelet-selective anti-thrombotic agent (Langford et al, 1994). In addition, the reported roles of GSNO in activation of cell survival signaling cascades mediated by dynamin-2, phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK), and Bcl-2, and in inhibitions of proapoptotic caspase activation (Ju et al, 2005; Kang-Decker et al, 2007; Lowenstein, 2007; Zeigler et al, 2003) and pro-inflammatory cell signaling cascades (Kim et al, 2014; Prasad et al, 2007; Won et al, 2013) further suggest that exogenous GSNO targets various anti-inflammatory and cell survial signaling pathways and is protective in various neurological disease conditions, such as as stroke, traumatic brain injury, and spinal cord injury (Khan et al, 2005; Khan et al, 2011; Khan et al, 2015; Shunmugavel et al, 2012). In this study, we observed that systemic GSNO treatment attenuated the tau hyperphosphorylation and neurodegeneration in rat model of pBCCAO.…”

Simvastatin Ameliorates Cauda Equina Compression Injury in a Rat Model of Lumbar Spinal Stenosis

“…Following deparafinization, rehydration and antigen unmasking the tissue sections were blocked in Tris-sodium buffer with 0.5 % blocking reagent (TNB, supplied with TSA-Direct kit; NEN Life Sciences, Boston MA) for 30 min as described previously (Shunmugavel et al 2012a). Thesections were probed with anti activated microglia (CD68), cytotoxic T cell (CD8: Santa Cruz Biotechnology Inc. CA), glial fibrillary acidic protein (GFAP) and tumor necrosis factor alpha (TNF-α) antibodies.…”

Histopathological and Follicular Atresia Assessment of Rat’s Ovarian Tissue Following Experimental Chronic Spinal Cord Injury

“…Therefore, the SCI disconnects oncoming signaling transport from gonads to the brain, which cut off the liberation of gonadotropin from the hypothalamus and lead to hypogonadism of patients with SCI (17,18). Although the ovaries are transmitted with both the vagus nerve and the spinal cord branches, the continuaion of usual ovarian action after SCI could be mainly due to the preservation of neuronal tissue of the spinal cord.…”

“…Although the ovaries are transmitted with both the vagus nerve and the spinal cord branches, the continuaion of usual ovarian action after SCI could be mainly due to the preservation of neuronal tissue of the spinal cord. Hence, interruptions in signaling following SCI changes ovarian physiology via inflammation and apoptosis (17,18).…”