Abstract
Spinal cord injury (SCI) is involved with abnormal expression of miRNAs (miRs) which are responsible for some IIry injury responses which include apoptosis, inflammation and oxidative stress. Mechanisms involving miRs induced apoptosis still needs to be investigated. In the present work we developed a rat model of SCI, followed by microarray analysis for expression of miRs at various time points after SCI. The locomotor activity was assessed by Basso, Beattie and Bresnahan score, lesion volume was analyzed by cresyl violet staining and TUNEL staining for extent of apoptosis at various time points of post SCI. Numbers of miRs were altered after 2 weeks of SCI among which miR-466c-3p was the most significantly down-regulated. Transfection with miR-466c-3p mimics caused overexpression of miR-466c-3p, also improvement in functional recovery, decrease in apoptosis of neuronal cells and lesion size was observed in SCI rats. The Luciferase assay suggested that miR-466c-3p suppressed the expression of Bcl-2 (apoptosis regulator). It was also evidenced that upon restoring the levels of Bcl-2 with the help of pc-DNA3-Bcl-2 halted the attenuating action of miR-466c-3p in hydrogen peroxide exposed N9 microglia cells. The findings suggested that miR-466c-3p may inhibit mitochondrial apoptotic pathway via blocking Bcl-2 and cleaved capase-9/-3in rats after SCI. Altogether, the results suggested that miR-466c-3p may exert attenuating effect on functional recovery and inhibit the apoptosis of neuronal cells via halting the mitochondrial apoptosis cascade in SCI rats indicating that miR-466c-3p can be attractive therapeutic candidate in treating SCI.
Highlights
Spinal cord injury (SCI) is a common injury of spinal cord leading to permanent disability which includes paralysis, loss of sensitivity, control and movements in the lower part of body below the affected region (Chen et al 2016)
We found that expressions of large number of miRs were altered after 2 weeks inducing SCI and among them miR-466c-3p was the most significantly suppressed compared to the sham operated rats (Fig. 1a)
Up‐regulation of miR‐466c‐3p attenuated the functional activity and inhibited apoptosis of neuronal cells in SCI rats To evaluate the function of miR-466c-3p in SCI induced rats, the SCI induced rats were treated with miR-466c-3p mimics given by intrathecal route
Summary
Spinal cord injury (SCI) is a common injury of spinal cord leading to permanent disability which includes paralysis, loss of sensitivity, control and movements in the lower part of body below the affected region (Chen et al 2016). Apoptosis is a phenomenon in cells called as programmed cell death; it is an important process which affects the neuronal tissue damage after SCI (Kawabata et al 2010). Earlier it has been reported that both mitochondrial pathway and death receptor cause apoptosis (Li et al 2000). Cytochrome-c along with deoxy ATP and apoptosis protease triggering factor-1 converts cleaved pro-caspase-9 into active-caspase-9 in the cytosol (Li et al 2004). This active-caspase-9 causes cleavage of caspase-3/-6/-7 (Nicholson and Thornberry 1997). The release of cytochrome-c is an important step for the activation of pro-caspase-9 in apoptosis of cells
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