Endorepellin downregulation promotes angiogenesis after experimental traumatic brain injury

Endorepellin plays a key role in the regulation of angiogenesis,but its effects on angiogenesis after traumatic brain injury are unclear.This study explored the effects of endorepellin on angiogenesis and neurobehavioral outcomes after traumatic brain injury in mice.Mice were randomly divided into four groups:sham,controlled cortical impact only,adeno-associated virus(AAV)-green fluorescent protein,and AAV-shEndorepellin-green fluorescent protein groups.In the controlled cortical impact model,the transduction of AAV-shEndorepellin-green fluorescent protein downregulated endorepellin while increasing the number of CD31+/Ki-67+proliferating endothelial cells and the functional microvessel density in mouse brain.These changes resulted in improved neurological function compared with controlled cortical impact mice.Western blotting revealed increased expression of vascular endothelial growth factor and angiopoietin-1 in mice treated with AAV-shEndorepellin-green fluorescent protein.Synchrotron radiation angiography showed that endorepellin downregulation promoted angiogenesis and increased cortical neovascularization,which may further improve neurobehavioral outcomes.Furthermore,an in vitro study showed that downregulation of endorepellin increased tube formation by human umbilical vein endothelial cells compared with a control.Mechanistic analysis found that endorepellin downregulation may mediate angiogenesis by activating vascular endothelial growth factor-and angiopoietin-1-related signaling pathways.

Microelectrode array recordings of excitability of low Mg^(2+)-induced acute hippocampal slices

Neuronal connections can be detected by neuronal network discharges in hippocampal neurons cultured on multi-electrodes.However,the multi-electrode-array（MEA）has not been widely used in hippocampal slice culture studies focused on epilepsy.The present study induced spontaneous synchronous epileptiform activity using low Mg2＋artificial cerebrospinal fluid on acute hippocampal slices to record hippocampal discharges with MEA.Results showed that burst duration and average number of spikes in a burst were significantly greater in the CA3 compared with dentate gyrus and CA1 areas.In Schaffer cut-off group,CA1 area discharges disappeared,but synchronous discharges remained in the CA3 area.Moreover,synchronous discharge frequency in the Schaffer cut-off group was similar to control.However,burst duration and average number of spikes in a burst were significantly decreased compared with control（P 〈 0.05）.Results demonstrated that highest neuronal excitability occurred in the CA3 area,and synchronous discharges induced by low Mg2＋originated from the CA3 region.

PAID study design on the role of PKC activation in immune/inflammation-related depression:a randomised placebo-controlled trial protocol

Background Inflammation that is mediated by microglia activation plays an important role in the pathogenesis of depression.Microglia activation can lead to an increase in the levels of proinflammatory cytokines,including TNF-α,which leads to neuronal apoptosis in the specific neural circuits of some brain regions,abnormal cognition and treatment-resistant depression(TRD).Protein kinase C(PKC)is a key regulator of the microglia activation process.We assume that the abnormality in PKC might result in abnormal microglia activation,neuronal apoptosis,significant changes in emotional and cognitive neural circuits,and TRD.In the current study,we plan to target at the PKC signal pathway to improve the TRD treatment outcome.Methods and analysis This is a 12-week,ongoing,randomised,placebo-controlled trial.Patients with TRD(N=180)were recruited from Shanghai Mental Health Center,Shanghai Jiao Tong University.Healthy control volunteers(N=60)were recruited by advertisement.Patients with TRD were randomly assigned to‘escitalopram+golimumab(TNF-αinhibitor)’,‘escitalopram+calcium tablet+vitamin D(PKC activator)’or‘escitalopram+placebo’groups.We define the primary outcome as changes in the 17-item Hamilton Depression Rating Scale(HAMD-17).The secondary outcome is defined as changes in anti-inflammatory effects,cognitive function and quality of life.Discussion This study might be the first randomised,placebo-controlled trial to target at the PKC signal pathway in patients with TRD.Our study might help to propose individualised treatment strategies for depression.Trial registration number The trial protocol is registered with ClinicalTrials.gov under protocol ID 81930033 and ClinicalTrials.gov ID NCT04156425.

THE EFFECTS OF DEPRENYL AND 1-METHYL-4-PHENYL-1, 2, 3, 6-TETRAHYDROPYRIDINE (MPTP) ON 2-DEOXYGLUCOSE UPTAKE IN THE MOUSE BRAIN

~3H-2-deoxyglucose (2-DG) autoradiographic technique was used to study the ef feets of a monoamine-oxidase-B (MAO-B) inhibitor deprenyl and the neurotoxin Ⅰ-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) on 2-DG uptake in the mouse brain. Following MPTP intoxication, 2-DG uptake was increased in the substantia nigra and lo(?)us ceruleus. At the same time, obvious abnormal behavior of the animals was induced. In the mice pretreated with deprenyl, 2-DG uptake was similar to that of control animal. Ab normal behavior. though present, was significantly milder than in mice given MPTP alone. It is concluded that MPTP interferes with the glucose metabolism in the substantia nigra and locus ceruleus and induces remarkable abnormal behavioral syndrome of mice. These deleterious effects can be blocked by pretreatment with deprenyl.

MADOPAR-INDUCED DYSKINESIA IN 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE (MPTP) HEMIPARKINSONIAN MONKEY MODEL

Infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the right common carotid artery produced hemiparkinsonian syndrome on contralateral limbs in 5 rhesus monkeys. The hemiparkinsonian syndrome produced responded to madopar medication and the circling motion changed from toward the MPTP-treated side to away from the MPTP-treated side. Long term use of madopar developed a peak-dose dyskinesia of the face and limbs at the contralateral side. The toxic effect of MPTP was confirmed biochemically by reduction of nigrostriatal DA and histologically by degeneration of nigral neurons on the MPTP-treated side. It is concluded that this hemiparkinsonian monkey model will be of value in the elucidation of the neural mechanism underlying L-DOPA or DA agonists induced dyskinesia in Parkinson’s disease and in the search for newer methods of treatment which would produce less dyskinesia.

Spatiotemporal dynamics of high-K^+-induced epileptiform discharges in hippocampal slice and the effects of valproate

The epileptic seizure is a dynamic process involving a rapid transition from normal activity to a state of hypersynchronous neuronal discharges. Here we investigated the network properties of epileptiform discharges in hippocampal slices in the presence of high K ＋ concentration （8.5 mmol/L） in the bath, and the effects of the anti-epileptic drug valproate （VPA） on epileptiform discharges, using a microelectrode array. We demonstrated that epileptiform discharges were predominantly initiated from the stratum pyramidale layer of CA3a-b and propagated bi-directionally to CA1 and CA3c. Disconnection of CA3 from CA1 abolished the discharges in CA1 without disrupting the initiation of discharges in CA3. Further pharmacological experiments showed that VPA at a clinically relevant concentration （100 μmol/L） suppressed the propagation speed but not the rate or duration of high-K＋-induced discharges. Our findings suggest that pacemakers exist in the CA3a-b region for the generation of epileptiform discharges in the hippocampus. VPA reduces the conduction of such discharges in the network by reducing the propagation speed.

Microglia-Derived NLRP3 Activation Mediates the Pressor Effect of Prorenin in the Rostral Ventrolateral Medulla of Stress-Induced Hypertensive Rats

Increased microglial activation and neuroinflammation within autonomic brain regions such as the rostral ventrolateral medulla(RVLM)have been implicated in stress-induced hypertension(SIH).Prorenin,a member of the brain renin-angiotensin system(RAS),can directly activate microglia.The present study aimed to investigate the effects of prorenin on microglial activation in the RVLM of SIH rats.Rats were subjected to intermittent electric foot-shocks plus noise,this stress was administered for 2 h twice daily for 15 consecutive days,and mean arterial pressure(MAP)and renal sympathetic nerve activity(RSNA)were monitored.The results showed that MAP and RSNA were augmented,and this paralleled increased pro-inflammatory phenotype(M1)switching.Prorenin and its receptor(PRR)expression and the NLR family pyrin domain containing 3(NLRP3)activation were increased in RVLM of SIH rats.In addition,PLX5622(a microglial depletion agent),MCC950(a NLRP3 inhibitor),and/or PRO20(a(Pro)renin receptor antagonist)had antihypertensive effects in the rats.The NLRP3 expression in the RVLM was decreased in SIH rats treated with PLX5622.Mito-tracker staining showed translocation of NLRP3 from mitochondria to the cytoplasm in proreninstimulated microglia.Prorenin increased the ROS-triggering M1 phenotype-switching and NLRP3 activation,while MCC950 decreased the M1 polarization.In conclusion,upregulated prorenin in the RVLM may be involved in the pathogenesis of SIH,mediated by activation of the microglia-derived NLRP3 inflammasome.The link between prorenin and NLRP3 in microglia provides insights for the treatment of stress-related hypertension.

Predictors of outcome in the surgical treatment for epilepsy

Background Knowledge about factors influencing the prognosis of resective epilepsy surgery can be used to identify which patients are most suitable for surgical treatment. The aim of this study was to identify preoperative prognostic factors associated with the chance of achieving long-term seizure freedom. Methods We retrospectively reviewed seizure outcomes and clinical, electroencephalography （EEG）, magnetic resonance imaging （MRI）, histopathology, and surgical variables from 99 epilepsy surgery patients with at least one year of postoperative follow-up. Seizure outcomes were categorized based on the modified classification by the International League Against Epilepsy. Results We found that the seizure-free rate was 27.9% after one year, and that it stabilized at about 20.0% between two and six years after surgery. Univariate analysis showed that medial temporal lobe epilepsy with hippocampal sclerosis, MRI with visible focal lesions concordant with EEG, and regional ictal EEG and electrocorticography patterns were associated with a favorable surgical outcome. On the other hand, seizure recurrence within six months, incomplete focus resection, and surgical complications were associated with a poor outcome. Multivariate analysis showed that medial temporal lobe epilepsy with hippocampal sclerosis and MRI with visible focal lesions were independent presurgical predictors of a favorable outcome （P 〈0.01）. Seizure recurrence within six months was the only significant independent predictor associated with a poor outcome （P〈0.01）. Conclusion Hippocampal sclerosis and abnormal MRI findings are strongly associated with a favorable surgical outcome, whereas seizure recurrence within six months is associated with a poor outcome.

Cortical encephalitis with overlapping anti-N-methyl-D-aspartate receptor and anti-myelin oligodendrocyte glycoprotein antibodies:report of two cases

To the Editor:Anti-N-methyl-D-aspartate receptor(NMDAR)encephalitis(NMDARE)is a potentially lethal autoimmune disease.Anti-myelin oligodendrocyte glyco-protein(MOG)antibody(Ab)could represent a diagnostic biomarker for a distinct spectrum of central nervous system(CNS)inflammatory demyelinating diseases(IDDs).Herein,we report two cases,positive for both NMDAR-Ab and MOG-Ab,which was presented with cortical encephalitis and subsequent demyelination.

Different distributions of nerve demyelination in chronic acquired multifocal polyneuropathies

Background:Multifocal motor neuropathy(MMN),Lewis-Sumner syndrome(LSS),and many chronic inflammatory demyelinating polyradiculoneuropathies(CIDPs)are representative of acquired multifocal polyneuropathy and are characterized by conduction block(CB).This retrospective study aimed to investigate the demyelinating distribution and the selective vulnerability of MMN,LSS,and CIDP with CB(CIDP-CB)in nerves.Methods:Fifteen LSS subjects(107 nerves),24 MMN subjects(176 nerves),and 17 CIDP-CB subjects(110 nerves)were included.Their clinical information was recorded,blood and cerebrospinal fluid tests were conducted,and nerve conductions of the median,ulnar,radial,peroneal,and tibial nerves were evaluated.CB,temporal dispersion,distal motor latency(DML),and F-wave latency were recorded,and nerve conduction velocity,terminal latency index,and modified F-wave ratio were calculated.Results:CB was more likely to occur around the elbow in CIDP-CB than in MMN(78.6%vs.6.8%,P<0.01)but less likely to occur between the wrist and the elbow than in LSS(10.7%vs.39.3%,P<0.05).Tibial nerve CB was most frequently observed in MMN(47.4%,P<0.05).CIDP-CB was characterized by a prolonged DML in all nerves,and slow motor nerve velocity of the upper limb was significant when CB nerves were excluded(P<0.05).Conclusions:We report the different distributions of segmental and diffuse demyelination of the ulnar and tibial nerves in LSS,MMN,and CIDP-CB.These distinct distributions could help in differentiating among these conditions.

BIOCHEMICAL AND CIRCLING BEHAVIORAL ALTERATIONS FOLLOWING INJECTION OF MPTP INTO SNC IN RAT

MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) is a byproduct formed during the synthesis of a meperidine analog. Davis (1979) and Langston (1983) reported a group of drug addicts who developed classical Parkinsonism after self-administration of a mixture containing MPTP, their pathological and biochemical

Study on hippocampal volume with quantitative 3T magnetic resonance imaging in Chinese patients with epilepsy

Background It was still rare for the quantitative magnetic resonance imaging （MRI） research of regional changes in hippocampus sclerosis （HS） in Chinese patients with epilepsy. This study aimed to study the hippocampal volumes （HVs） with quantitative MRI measurement in Chinese patients with epilepsy. Methods Forty-six Chinese patients with epilepsy （intractable epilepsy （IE）, n=21; non-intractable epilepsy （NIE）, n=25） and 25 normal controls were collected between July 2007 and March 2008. All of the subjects underwent a 3T high-resolution MRI with oblique coronal thin sections oriented perpendicular to the hippocampal long axis. Hippocampal structures were assessed by visual detection, and HVs were quantitatively studied with a Picture Archiving and Communication System （PACS）. Results Our study suggested that there was no significant difference in gender （P 〉0.05） while the right hippocampal head volume （HHV）, hippocampal body volume （HBV）, and the whole hippocampal volume （HCV） were greater than the left one （P 〈0.05）, but no significant difference was found in bilateral hippocampal tail volume （HTV） （P 〉0.05） in normal controls. That unilateral/diffuse （64%/21%） and bilateral/focal （86%/20%） hippocampal atrophy （HA） were significant in IE and NIE patients, respectively. Anterior hippocampus, especially HHV （26% in IE and 20% in NIE） and HBV （29% in IE and 12% in NIE）, had more significant atrophy than the HTV （5% in IE and 0% in NIE） in patients with epilepsy.