Stimulation of functional recovery via the mechanisms of neurorepair by S-nitrosoglutathione and motor exercise in a rat model of transient cerebral ischemia and reperfusion

Abstract

Purpose Stroke disability stems from insufficient neurorepair mechanisms. Improvement of functions has been achieved through rehabilitation or therapeutic agents. Therefore, we combined exercise with a neurovascular protective agent, S-nitrosoglutathione (GSNO), to accelerate functional recovery. Methods Stroke was induced by middle cerebral artery occlusion for 60 min followed by reperfusion in adult male rats. Animals were treated with vehicle (IR group), GSNO (0.25 mg/kg, GSNO group), rotarod exercise (EX group) and GSNO plus exercise (GSNO+EX group). The groups were studied for 14 days to determine neurorepair mechanisms and functional recovery. Results Treated groups showed reduced infarction, decreased neuronal cell death, enhanced neurotrophic factors, and improved neurobehavioral functions. However, the GSNO+EX showed greater functional recovery (p<0.05) than the GSNO or the EX group. A GSNO sub group, treated 24 hours after IR, still showed motor function recovery (p<0.001). The protective effect of GSNO or exercise was blocked by the inhibition of Akt activity. Conclusions GSNO and exercise aid functional recovery by stimulating neurorepair mechanisms. The improvements by GSNO and exercise depend mechanistically on the Akt pathway. A combination of exercise and GSNO shows greater functional recovery. Improved recovery with GSNO, even administered 24 hours post-IR, demonstrates its clinical relevance.

Targeting the nNOS/peroxynitrite/calpain system to confer neuroprotection and aid functional recovery in a mouse model of TBI

“…This disturbed NO metabolome in TBI is supported by previous studies from our laboratory in TBI (Khan et al, 2011) and stroke (Khan et al, 2012; Khan et al, 2015b) and the current results, which show increased enzymatic nNOS activity (Fig 1B) and sustained high levels of peroxynitrite for a prolonged periods (Figs 2D–d and 4B–b). We investigated the mechanisms of the efficacy of GSNO for TBI therapy because it corrected not only the disturbed NO metabolome (Fig 1) and NO/S-nitrosylation-based cellular functions (Khan et al, 2005; Khan et al, 2011; Khan et al, 2015a; Sakakima et al, 2012) but also provided neuroprotection and improved neurological functions, as shown in Fig 5.…”

“…The NeuN immunostaining indicates number of neurons. Paraffin-embedded brain sections from the formalin-fixed brain tissues, processed at 14 days after CCI, were used to stain with Nissl and the staining was performed according to classical histology methods as previously described from our laboratory (Khan et al, 2015a; Sakakima et al, 2012). Cells that contained Nissl substance were considered to be viable neurons.…”

“…Percent of NeuN positive area were determined as previously described from our laboratory (Sakakima et al, 2012) and viable neurons from Nissl staining were quantified by manually counting cells as previously described from our and other laboratories (Khan et al, 2015a; Zhu et al, 2014) in the traumatic penumbra area using an Olympus microscope. Histological and immunohistological analysis was performed by an observer blinded to the identity of groups as previously described from our laboratory (Khan et al, 2015a; Sakakima et al, 2012). …”

“…Animals were pre-trained for 3 days before CCI. We routinely use this task, as published for IR and TBI studies (Khan et al, 2009; Khan et al, 2015a; Sakakima et al, 2012). …”

Motor Skill Training Promotes Sensorimotor Recovery and Increases Microtubule-Associated Protein-2 (MAP-2) Immunoreactivity in the Motor Cortex after Intracerebral Hemorrhage in the Rat

“…Experimental rehabilitative therapies may influence synaptogenesis, neurogenesis, and neuron and glial responses in addition to functional recovery [6, 7]. Although positive effects of skilled training as a rehabilitative modality have been reported, neurobiological mechanisms that support motor and functional recovery are not completely elucidated [8, 9].…”