Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammation.

BACKGROUND: Midkine (MK) is a multifunctional cytokine found upregulated in the brain in the presence of different disorders characterized by neuroinflammation, including neurodegenerative disorders and ischemia. The neuroinflammatory response to traumatic brain injury (TBI) represents a key secondary injury factor that can result in further neuronal injury. In the present study, we investigated the role of endogenous MK in secondary injury, including neuroinflammation, immune response, and neuronal apoptosis activity, after TBI. METHODS: Wild type (Mdk+/+) and MK gene deficient (Mdk-/-) mice were subjected to fluid percussion injury for TBI models and compared at 3, 7, and 14 days after TBI, in terms of the following: brain tissue loss, neurological deficits, microglia response, astrocytosis, expression of proinflammatory M1 and anti-inflammatory M2 microglia/macrophage phenotype markers, and apoptotic activity. RESULTS: As opposed to Mdk+/+ mice, Mdk-/- mice reported a significantly reduced area of brain tissue loss and an improvement in their neurological deficits. The ratios of the Iba1-immunoreactive microglia/macrophages in the perilesional site were significantly decreased in Mdk-/- than in the Mdk+/+ mice at 3 days after TBI. However, the ratios of the glial fibrillary acidic protein immunoreactive area were similar between the two groups. The M1 phenotype marker (CD16/32) immunoreactive areas were significantly reduced in Mdk-/- than in the Mdk+/+ mice. Likewise, the mRNA levels of the M1 phenotype markers (TNF-α, CD11b) were significantly decreased in Mdk-/- mice than in Mdk+/+ mice. Furthermore, flow cytometry analysis identified the M2 markers, i.e., CD163+ macrophages cells and arginase-1+ microglia cells, to be significantly higher in Mdk-/- than in Mdk+/+ mice. Finally, the ratios of apoptotic neurons were significantly decreased in the area surrounding the lesion in Mdk-/- than in Mdk+/+ mice following TBI. CONCLUSION: Our findings suggest that MK-deficiency reduced tissue infiltration of microglia/macrophages and altered their polarization status thereby reducing neuroinflammation, neuronal apoptosis, and tissue loss and improving neurological outcomes after TBI. Therefore, targeting MK to modulate neuroinflammation may represent a potential therapeutic strategy for TBI management.

Effects of different remote ischemia perconditioning methods on cerebral infarct volume and neurological impairment in rats.

Remote ischemic perconditioning (RIPerC) is a novel neuroprotective method against cerebral infarction that has shown efficacy in animal studies but has not been consistently neuroprotective in clinical trials. We focused on the temporal regulation of ischemia-reperfusion by RIPerC to establish an optimal method for RIPerC. Rats were assigned to four groups: 10 min ischemia, 5 min reperfusion; 10 min ischemia, 10 min reperfusion; 5 min ischemia, 10 min reperfusion; and no RIPerC. RIPerC interventions were performed during ischemic stroke, which was induced by a 60-min left middle cerebral artery occlusion. Infarct volume, sensorimotor function, neurological deficits, and cellular expressions of brain-derived neurotrophic factor (BDNF), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and caspase 3 were evaluated 48 h after the induction of ischemia. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) was also performed. RIPerC of 10 min ischemia/10 min reperfusion, and 5 min ischemia/10 min reperfusion decreased infarct volume, improved sensorimotor function, decreased Bax, caspase 3, and TUNEL-positive cells, and increased BDNF and Bcl-2 expressions. Our findings suggest RIPerC with a reperfusion time of approximately 10 min exerts its neuroprotective effects via an anti-apoptotic mechanism. This study provides important preliminary data to establish more effective RIPerC interventions.

Acute changes in cortical activation during active ankle movement after whole-body vibration for spasticity in hemiplegic legs of stroke patients: a functional near-infrared spectroscopy study.

Background: A recent study revealed that whole-body vibration (WBV) tends to decrease spasticity in stroke-related hemiplegic legs. However, acute changes in cortical activation after WBV are unclear.Objective: To examine whether WBV induces acute changes in sensorimotor cortical activation in patients with stroke-related hemiplegic legs.Methods: Eleven stroke patients (mean age 52.6 [SD 15.4] years; median time after stroke 3 [25th and 75th percentiles; 3 and 10.5, respectively] months) participated in a comparative before-and-after intervention trial. Six healthy adults were also studied. WBV at 30 Hz was applied for 5 min to the hamstrings, gastrocnemius, and soleus muscles. Spasticity was assessed according to the modified Ashworth scale (MAS). Active and passive range of motion (A-ROM and P-ROM, respectively) were also measured. Change in Oxy-Hb concentration in bilateral sensorimotor cortex associated with voluntary ankle dorsiflexion of the affected limb was assessed via functional near-infrared spectroscopy (fNIRS) before and immediately after WBV.Results: MAS score, A-ROM, and P-ROM improved immediately after WBV. In the patients, while there was no significant interaction between effects of region (ipsilesional and contralesional sensorimotor cortex) and the WBV intervention (before and immediately after WBV) (F1,10 = 0.702, p = .422), there was a significant main effect of the WBV intervention (F1,10 = 6.971, p = .025). In the healthy participants, there was no association with the WBV intervention or region.Conclusions: In patients with stroke-related spastic-hemiplegic legs, WBV might result not only in clinical improvement but also in acute increase in sensorimotor cortical activation.