Staged suppression of microglial autophagy facilitates regeneration in CNS demyelination by enhancing the production of linoleic acid.

Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic-lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic-lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic-lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.

De qi, a threshold of the stimulus intensity, elicits the specific response of acupoints and intrinsic change of human brain to acupuncture.

Objectives. De qi is the subjective constellation of sensations perceived by the acupuncturists and patients as described in several literatures, but the absence of quantitative evaluation methods in de qi restricts the use of acupuncture treatment widely in the world. In the present study, we tried to investigate the intrinsic property of de qi is and how evaluate it quantitatively. Methods. 30 healthy adult volunteers were determined to investigate intrinsic changes in the human body after acupuncture with de qi. Results. Acupuncture treatment with de qi apparently increased acupoint blood flow, tissue displacement, and the amplitude of myoelectricity after de qi on acupoints. Furthermore, acupuncture treatment induced fMRI signal increase/decrease in different brain regions although no significant change in electroencephalography. Interpretation. The intrinsic change of the subjects representing the specific response of acupoints and human brain to acupuncture indicated that de qi might be evaluated quantitatively by those above aspects, which facilitated the confirmation in validity and propagation of this treatment modality widely in the world.

Involvement of connexin 43 in acupuncture analgesia.

BACKGROUND: Connexin 43 (Cx43) is one of the major components of human keratinocyte gap junctions. To study whether gap junctional intercellular communication participates in the transfer of acupoint signals and acupuncture analgesia, the expression of Cx43 was studied in Zusanli (ST36) acupoints compared with control non-acupoint regions in rats after acupuncture. In addition, Cx43 heterozygous gene knockout mice were used to further explore the relationship between Cx43 and acupuncture analgesia. METHODS: The expression of Cx43 was detected by immunohistochemistry, immunoblotting, and RT-PCR for the Cx43 protein and mRNA. The influence of the Cx43 gene knockout on acupuncture analgesia was measured by a hot plate and observing the writhing response on Cx43 heterozygous gene knockout mice. RESULTS: Immunohistochemistry showed abundant Cx43 expression in some cells in the skin and subcutaneous tissue of rat ST36 acupoints. The mRNA and protein levels of Cx43 in acupoints were significantly higher than those in the control points in the non-acupuncture group, and even more so after acupuncture. The hot plate and writhing response experiments showed that partial knockout of the Cx43 gene decreased acupuncture analgesia. CONCLUSION: Cx43 expression and acupuncture analgesia showed a positive correlation.