Objective The hypoxic-ischemic(HI) cardio-cerebral damage caused by cardiac arrest in perioperative period is the main cause of acute and chronic disability in children patients.To investigate role of mitochondrial dysfunction in hypoxic-ischemic brain damage of mice.Methods The hypoxic-ischemic mice model was established by the bilateral carotid artery occlusion and hypoxia treatment.The neurobehavior of mice in HI model group,sham-operated group,and comparative group were evaluated within 48 hours after operation.After 48 hours,the mice were killed to evaluate the brain water content,mitochondria content,swelling,antioxidant capacity,and respiratory function.Results Within 0,24 hours after operation,the abnormal rate of the neurobehavior of HI model mice was 83.33％,which was significantly higher than comparative and sham-operated groups.The water content of right brain was significantly increased evidently compared to the other two groups (P ＜ 0.05).The content and swelling of mitochondria in brain were increased.The activity of superoxide dismutase (SOD),the glutathione (GSH) content,respiratory state 3 (ST3),and respiration control of rate (RCR) were significantly decreased; while the content of malondialdehyde (MDA) and ST4 were significantly increased (P ＜ 0.05).Conclusions The brain tissue showed different swelling,the mitochondrial function occurred disorder,which might play an important role in hypoxic-ischemic brain damage of mice.

Objective To explore the effects of application calcitonin gene related peptide(CGRP) in cisterna magna on cerebral vasospasm after experimental subarachnoid hemorrhage (subarachnoid hemorrhage,SAH) in rat models.Methods 64 male Wistar rats were randomly divided into 4 groups.Group A was normal control group.After the subarachnoid hemorrhage models were established,group B,C,D were given normal saline,CGRP and adenovirus CGRP through cisterna magna respectively.White blood cells in cerebrospinal fluid were detected by automatic blood analyzer,CGRP activity was detected by enzyme linked immunosorbent assay,circulating endothelial cells were observed through laser scanning confocal microscope and parietal cortex regional cerebral blood flow were observed by laser doppler flowmeter.Basilar artery vasospasm and arterial blood gas analysis were detected by digital subtraction angiography and blood gas analyzer respectively.Results Before and after administration,there were no statistical differences in white blood cells and artery blood gas among the 4 groups (both P＞ 0.05).After administration 48 h,compared with group A,concentrations of CGRP in cerebrospinal fluid group B (0.006±0.002) did not increase (P＞0.05),but increased 200 times in Group C ((1.160±0.170) nmol/L,P＜0.05)and nearly 400 times in group D ((2.071±0.412) nmol/L,P＜0.05).Peripheral blood circulating endothelial cells count:after administration 48 h,group C((5.56±0.61) ind/0.9 μL) was less than in group B((9.94± 0.73) ind/0.9 μL).Group D((5.16±0.61) ind/0.9 μL) was less than group C(P＜0.01).Regional cerebral blood flow:after administration,compared with group B,cerebral blood flow of group C and group D increased,and the differences were both statistically significant (P＜0.01).Basilar artery diameter was detected after administration 12 h,group D ((1.000±0.025) mm) was 13％ bigger than group B ((0.670±0.028)mm,P＜0.05),3％ bigger than group C ((0.900±0.023) mm) (P＞0.05).Conclusion Cerebral vasospasm after SAH can be effectively improved by administration CGRP in cisterna magna.Adenovirus CGRP effect is better than CGRP.

With the rapid development of biotechnology, therapeutic peptide has been a hot area in the central nervous system drugs due to its features of easy to design and target specificity. However, therapeutic peptide is difficult to cross the blood brain barrier into the central nervous system and target cells, coupled with its in vivo instability, which seriously restricts its application in central nervous system diseases. This review focuses on the progress of therapeutic peptides across the blood brain barrier targeting the central nervous system, compares and analyses the methods of increasing therapeutic peptides penetration, specificity and stability in combination with other molecules, in order to provide help for the development of central nervous system drugs.

Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a^-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a^-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.
Animals ; Mice ; Amputation, Surgical ; Chronic Pain/pathology* ; Disease Models, Animal ; Ganglia, Spinal/pathology* ; Hyperalgesia/etiology* ; Ion Channels/metabolism* ; Macrophages ; Neuroma/pathology*