Association of medullary reticular formation ventral part with spasticity in mice suffering from photothrombotic stroke.

Strokes cause spasticity via stretch reflex hyperexcitability in the spinal cord, and spastic paralysis due to involuntary muscle contraction in the hands and fingers can severely restrict skilled hand movements. However, the underlying neurological mechanisms remain unknown. Using a mouse model of spasticity after stroke, we demonstrate changes in neuronal activity with and without electrostimulation of the afferent nerve to induce the stretch reflex, measured using quantitative activation-induced manganese-enhanced magnetic resonance imaging. Neuronal activity increased within the ventral medullary reticular formation (MdV) in the contralesional brainstem during the acute post-stroke phase, and this increase was characterised by activation of circuits involved in spasticity. Interestingly, ascending electrostimulation inhibited the MdV activity on the stimulation side in normal conditions. Moreover, immunohistochemical staining showed that, in the acute phase, the density of GluA1, one of the α-amino-3 hydroxy­5 methyl -4 isoxazolepropionic acid receptor (AMPAR) subunits, at the synapses of MdV neurons was significantly increased. In addition, the GluA1/GluA2 ratio in these receptors was altered at 2 weeks post-stroke, confirming homeostatic plasticity as the underlying mechanisms of spasticity. These results provide new insights into the relationship between impaired skilled movements and spasticity at the acute post-stroke phase.

Protective effects of hachimijiogan (HJG), a Japanese Kampo medicine, on cancer cachectic muscle wasting in mice.

Myogenesis is required to generate skeletal muscle tissue and to maintain skeletal muscle mass. Decreased myogenesis under various pathogenic conditions results in muscular atrophy. Through a small screening of Japanese traditional (Kampo) medicines, hachimijiogan (HJG) was shown to promote the myogenic differentiation of C2C12 myoblasts through the upregulation of myogenin. In tumor-bearing cancer-cachectic mice, HJG was also found to have a protective effect against cancer-cachectic muscle wasting. This effect was significant when HJG was administered in combination with aerobic exercise by treadmill running. Moreover, HJG ameliorated the cellular atrophy of C2C12 myotubes induced by treatment with conditioned medium derived from a colon-26 cancer cell culture. In addition, HJG suppressed H2O2-dependent myotube atrophy, suggesting that HJG could reverse the atrophic phenotypes by eliminating reactive oxygen species.

Aerobic Exercise Ameliorates Cancer Cachexia-Induced Muscle Wasting through Adiponectin Signaling.

Cachexia is a multifactorial syndrome characterized by muscle loss that cannot be reversed by conventional nutritional support. To uncover the molecular basis underlying the onset of cancer cachectic muscle wasting and establish an effective intervention against muscle loss, we used a cancer cachectic mouse model and examined the effects of aerobic exercise. Aerobic exercise successfully suppressed muscle atrophy and activated adiponectin signaling. Next, a cellular model for cancer cachectic muscle atrophy using C2C12 myotubes was prepared by treating myotubes with a conditioned medium from a culture of colon-26 cancer cells. Treatment of the atrophic myotubes with recombinant adiponectin was protective against the thinning of cells through the increased production of p-mTOR and suppression of LC3-II. Altogether, these findings suggest that the activation of adiponectin signaling could be part of the molecular mechanisms by which aerobic exercise ameliorates cancer cachexia-induced muscle wasting.

Median nerve injury does not contribute to early onset of decreased grip strength due to repetitive reaching and grasping tasks in rats.

BACKGROUND: Workplace risk factors, such as repetitive tasks, can cause work-related musculoskeletal disorders. In a rat model, decreased grip strength and median nerve injury develop following repetitive reaching and grasping tasks, involving negligible force. OBJECTIVE: We investigated whether median nerve injury is involved in the early onset of decreased grip strength due to such tasks METHODS: Sprague-Dawley rats were divided into: non-task-performing (0-week) and task-performing (1-, 2-, and 3-week) groups. After an initial training period, the task-performing groups continued to perform the task for 2 h/day, 3 days/week, for 1-3 weeks. Grip strength and relative muscle weight of the flexor digitorum superficialis (FDS) muscle were measured. Median nerve injury was evaluated by histopathology and immunohistochemistry. RESULTS: Grip strength of the reach limb (forelimb used in tasks) was significantly lower in the 3-week group compared with the other groups and was significantly lower than that of the non-reach limb in all groups. There were no significant differences in the relative FDS muscle weights of either limb among groups. No evidence of median nerve demyelination was observed and no cells expressed activating transcription factor-3, a specific marker of peripheral nerve injury, in the anterior horn of the spinal cord. CONCLUSION: Median nerve injury does not contribute to the decreased grip strength caused by 3 weeks of repetitive reaching and grasping tasks, involving negligible force, in rats.

Role of the BDNF-TrkB pathway in KCC2 regulation and rehabilitation following neuronal injury: A mini review.

In most mature neurons, low levels of intracellular Cl- concentrations ([Cl-]i) are maintained by channels and transporters, particularly the K+-Cl- cotransporter 2 (KCC2), which is the only Cl- extruder in most neurons. Recent studies have implicated KCC2 expression in the molecular mechanisms underlying neuronal disorders, such as spasticity, epilepsy and neuropathic pain. Alterations in KCC2 expression have been associated with brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB). The present review summarizes recent progress regarding the roles of Cl- regulators in immature and mature neurons. Moreover, we focus on the role of KCC2 regulation via the BDNF-TrkB pathway in spinal cord injury and rehabilitation, as prior studies have shown that the BDNF-TrkB pathway can affect both the pathological development and functional amelioration of spinal cord injuries. Evidence suggests that rehabilitation using active exercise and mechanical stimulation can attenuate spasticity and neuropathic pain in animal models, likely due to the upregulation of KCC2 expression via the BDNF-TrkB pathway. Moreover, research suggests that such rehabilitation efforts may recover KCC2 expression without the use of exogenous BDNF.