This study evaluated the efficacy of umbilical cord blood (UCB) cell for patients with cerebral palsy (CP) in a randomized, placebo-controlled, double-blind trial and also assessed factors and mechanisms related to the efficacy. Thirty-six children (ages 6 months to 20 years old) with CP were enrolled and treated with UCB or a placebo. Muscle strength and gross motor function were evaluated at baseline and 1, 3, and 6 months after treatment. Along with function measurements, each subject underwent (18)F-fluorodeoxyglucose positron emission tomography at baseline and 2 weeks after treatment. Cytokine and receptor levels were quantitated in serial blood samples. The UCB group showed greater improvements in muscle strength than the controls at 1 (0.94 vs. -0.35, respectively) and 3 months (2.71 vs. 0.65) after treatment (Ps<0.05). The UCB group also showed greater improvements in gross motor performance than the control group at 6 months (8.54 vs. 2.60) after treatment (P<0.01). Additionally, positron emission tomography scans revealed decreased periventricular inflammation in patients administered UCB, compared with those treated with a placebo. Correlating with enhanced gross motor function, elevations in plasma pentraxin 3 and interleukin-8 levels were observed for up to 12 days after treatment in the UCB group. Meanwhile, increases in blood cells expressing Toll-like receptor 4 were noted at 1 day after treatment in the UCB group, and they were correlated with increased muscle strength at 3 months post-treatment. In this trial, treatment with UCB alone improved motor outcomes and induced systemic immune reactions and anti-inflammatory changes in the brain. Generally, motor outcomes were positively correlated with the number of UCB cells administered: a higher number of cells resulted in better outcomes. Nevertheless, future trials are needed to confirm the long-term efficacy of UCB therapy, as the follow-up duration of the present trial was short.

The molecular events causing memory loss and neuronal cell death in Alzheimer's disease (AD) over time are still unknown. Here we found that picomolar concentrations of soluble oligomers of synthetic beta amyloid (Aβ42) aggregates incubated with BV2 cells or rat astrocytes caused a sensitised response of Toll-like receptor 4 (TLR4) with time, leading to increased production of TNF-α. Aβ aggregates caused long term potentiation (LTP) deficit in hippocampal slices and predominantly neuronal cell death in co-cultures of astrocytes and neurons, which was blocked by TLR4 antagonists. Soluble Aβ aggregates cause LTP deficit and neuronal death via an autocrine/paracrine mechanism due to TLR4 signalling. These findings suggest that the TLR4-mediated inflammatory response may be a key pathophysiological process in AD.

Two-pore domain K+ (K2P) channels have been shown to modulate neuronal excitability. The physiological role of TWIK-1, the first identified K2P channel, in neuronal cells is largely unknown, and we reported previously that TWIK-1 contributes to the intrinsic excitability of dentate gyrus granule cells (DGGCs) in mice. In the present study, we investigated the coexpression of TWIK-1 and TASK-3, another K2P member, in DGGCs. Immunohistochemical staining data showed that TASK-3 proteins were highly localized in the proximal dendrites and soma of DGGCs, and this localization is similar to the expression pattern of TWIK-1. TWIK-1 was shown to associate with TASK-3 in DGGCs of mouse hippocampus and when both genes were overexpressed in COS-7 cells. shRNA-mediated gene silencing demonstrated that TWIK-1/TASK-3 heterodimeric channels displayed outwardly rectifying currents and contributed to the intrinsic excitability of DGGCs. Neurotensin–neurotensin receptor 1 (NT–NTSR1) signaling triggered the depolarization of DGGCs by inhibiting TWIK-1/TASK-3 heterodimeric channels, causing facilitated excitation of DGGCs. Taken together, our study clearly showed that TWIK-1/TASK-3 heterodimeric channels contribute to the intrinsic excitability of DGGCs and that their activities are regulated by NT–NTSR1 signaling.