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An emerging body of data suggests that the early onset of Alzheimer's disease (AD) is associated with decreased brain-derived neurotrophic factor (BDNF). Because BDNF plays a critical role in the regulation of high-frequency synaptic transmission and long-term potentiation in the hippocampus, the up-regulation of BDNF may rescue cognitive impairments and learning deficits in AD. In the present study, we investigated the effects of hippocampal BDNF in a rat model of AD produced by a ventricle injection of amyloid-β1-42 (Aβ1-42). We found that a ventricle injection of Aβ1-42 caused learning deficits in rats subjected to the Morris water maze and decreased BDNF expression in the hippocampus. Chronic intra-hippocampal BDNF administration rescued learning deficits in the water maze, whereas infusions of NGF and NT-3 did not influence the behavioral performance of rats injected with Aβ1-42. Furthermore, the BDNF-related improvement in learning was ERK-dependent because the inhibition of ERK, but not JNK or p38, blocked the effects of BDNF on cognitive improvement in rats injected with Aβ1-42. Together, our data suggest that the up-regulation of BDNF in the hippocampus via activation of the ERK signaling pathway can ameliorate Aβ1-42-induced learning deficits, thus identifying a novel pathway through which BDNF protects against AD-related cognitive impairments. The results of this research may shed light on a feasible therapeutic approach to control the progression of AD.

Axonal dystrophy is a swollen and tortuous neuronal process that contributes to synaptic alterations occurring in Alzheimer’s disease (AD). Previous study identified that brain-derived neurotrophic factor (BDNF) binds to tropomyosin-related kinase B (TrkB) at the axon terminal and then the signal is propagated along the axon to the cell body and affects neuronal function through retrograde transport. Therefore, this study was designed to identify a microRNA (miRNA) that alters related components of the transport machinery to affect BDNF retrograde signaling deficits in AD. Hippocampus tissues were isolated from APP/PS1 transgenic (AD-model) mice and C57BL/6J wild-type mice and subject to nicotinamide adenine dinucleotide phosphate and immunohistochemical staining. Autophagosome-lysosome fusion and nuclear translocation of BDNF was detected using immunofluorescence in HT22 cells. The interaction among miR-204, BIR repeat containing ubiquitin-conjugating enzyme (BRUCE) and Syntaxin 17 (STX17) was investigated using dual luciferase reporter gene assay and co-immunoprecipitation assay. The expression of relevant genes and proteins were determined by RT-qPCR and Western blot analysis. Knockdown of STX17 or BRUCE inhibited autophagosome–lysosome fusion and impacted axon growth in HT22 cells. STX17 immunoprecipitating with BRUCE and co-localization of them demonstrated BRUCE interacted with STX17. BRUCE was the target of miR-204, and partial loss of miR-204 by inhibitor promoted autophagosome–lysosome fusion to prevent axon dystrophy and accumulated BDNF nuclear translocation to rescue BDNF/TrkB signaling deficits in HT22 cells. The overall results demonstrated that inhibition of miR-204 prevents axonal dystrophy by blocking BRUCE interaction with STX17, which unraveled potential novel therapeutic targets for delaying AD.

Background: Epilepsy is a common neurological disorder involving multiple genes and molecular pathways. Study of differentially expressed genes (DEGs) and hub genes related to epilepsy can help reveal the pathophysiologic basis and improve potential diagnostic and therapeutic strategies. Methods: Transcriptome data of two epilepsy datasets (GSE143272 and GSE32534) and single‐cell sequencing data (GSE201048) were collected from the Gene Expression Omnibus (GEO) database. Differential expression analysis was performed using Limma R package, and the hub genes were identified and analyzed utilizing STRING database and Cytoscape software. The clusterProfiler R package was used to perform gene function enrichment analysis and an epilepsy diagnostic model was constructed with the hub genes. The model performance was assessed according to receiver operating characteristic (ROC) curves. Results: Multiple DEGs linked to epilepsy were identified and 20 common DEGs between the two datasets were revealed. Eleven hub genes closely associated with epilepsy were identified by protein–protein interaction (PPI) network analysis. CD3D, CD3G, CTSW, and JCHAIN were consistently expressed in the GSE143272 and GSE32534 datasets and all showed a low expression in epilepsy samples. In particular, the diagnostic model developed with the four genes demonstrated a strong discriminatory ability in both datasets (all area under curve (AUC) > 0.7). Functional enrichment and single‐cell analysis revealed that these key genes were closely related to T cell function, suggesting that they may play an important role in the immune regulation of epilepsy. Conclusion: This study successfully identified four key genes linked to epilepsy, contributing to the molecular diagnosis of epilepsy.

ABSTRACT Purpose: Epilepsy is one of the most common neurological disorders with no effective drugs to prevent seizures or their progression. Iron modulation is a potential advanced treatment for seizures. We aim to investigate whether botulinum toxin type A (BoNT/A) can attenuate epilepsy‐induced neuronal death and maintain cognitive function by inhibiting ferroptosis. Method We established an epileptic rat model and intervened with BoNT/A to assess its influence on cognitive functions and the pathological damage of hippocampal tissues. Rat hippocampal neuronal cells were treated with magnesium‐free induction solution to establish an epileptic cell model and intervened using BoNT/A. Changes in ferrous ions (Fe2+), malondialdehyde (MDA), and glutathione (GSH) were detected in hippocampal tissues and cells. Western blot (WB) and RT‐qPCR were used to detect the protein expression of the iron death markers, including GPX4, ACSL4, and SLC7A11. Finding We found that BoNT/A attenuated epileptiform behavior and cognitive deficits and ameliorated hippocampal tissue damage in rats under lithium chloride‐pilocarpine‐induced epilepsy. In vitro BoNT/A treatment exerted potent neuroprotective effects on hippocampal neuronal cells treated by magnesium‐free induction solution. These protective effects were related to the regulation of ferroptosis mediated by the GPX4/ACSL4/SLC7A11 proteins. Conclusion: These results suggest that BoNT/A is effective in preventing epileptic neuronal iron death and attenuates cognitive dysfunction through the ferroptosis pathway. By establishing an epileptic rat model and in vitro epileptic cell model intervening with BoNT/A, we found that BoNT/A is effective in preventing epileptic neuronal iron death and attenuates cognitive dysfunction through the ferroptosis pathway.

Background Several RCT studies including ours, seem to prove the role of Botulinum toxin type A (BTX-A) in the treatment of trigeminal neuralgia (TN), but no standardized dosing regimen has been established. In our study, we compare two different methods of administration: single-dose or repeated-dose strategy which was most frequently applied over the years in our centre. Methods An open-label trail was conducted. One hundred patients with classic TN symptoms were recruited, and randomly and equally apportioned to single- or repeated-dose group. Patients in the single-dose group received a local BTX-A injection of 70 to 100 U. The repeated-dose group received an initial BTX-A injection of 50 to 70 U and then another of equal volume 2 weeks later. All patients were followed for 6 months. Results In the single- and repeated-dose groups, 44 and 37, respectively, completed the entire study. The groups were statistically similar in TN frequency, time between treatment and effect, time to peak effect, VAS scores, and rates of adverse reactions (latency and duration). However, the single-dose group experienced significantly longer duration of effect ( P  = 0.032). Conclusions The single- and repeated-dosing BTX-A regimens were largely comparable in efficacy and safety. This study suggests that repeated dosing has no advantage over single dosing of BTX-A for TN. Dosing should be adjusted for the individual patient.

BackgroundCervicocerebral artery dissection (CAD) is a major cause of ischemic stroke in young adults. There are many existing studies on determinants for CAD; however, they are still not totally defined. We conduct the study to further investigate the determinants for CAD based on ischemic stroke patients.Methods81 ischemic stroke patients with CAD were enrolled in the CAD stroke group and 84 ischemic stroke patients without CAD were enrolled in the non-CAD stroke group. Their clinical data, such as age, gender, vascular risk factors, headache and neck pain and clinical laboratory data, were collected to analyze the differences between the two groups.ResultsA total of 165 ischemic stroke patients were included. The mean age of CAD stroke group was (51.6 ± 12.4) years, and (55.5 ± 8.1) years in non-CAD stroke group, with a statistically significant difference (P = 0.017). The average level of triglycerides in CAD stroke group was (1.3 ± 0.7) mmol/L, and (1.7 ± 1.1) mmol/L in non-CAD stroke group, with a statistically significant difference (P = 0.012). There were 42.0% (34/81) of headache and neck pain in CAD stroke group and 22.6% (19/84) in non-CAD stroke group, with a statistically significant difference (P = 0.008). The key findings with significant difference were stratified and multivariate logistic regression analysis showed that age < 50 years old (OR 2.98, 95% CI 1.43–6.21, P = 0.004), triglycerides < 1.6 mmol/L (OR 3.51, 95% CI 1.69–7.27, P = 0.001) and headache and neck pain (OR 2.94, 95% CI 1.39–6.20, P = 0.005) showed a positive correlation with CAD.ConclusionIn the process of diagnosis and treatment of ischemic stroke, for patients with age < 50 years old, headache and neck pain and triglycerides < 1.6 mmol/L, the cervicocerebral artery dissection should be considered, and vascular imaging examination needs to be performed in time.

ObjectiveTo analyze the characteristics and relative factors of headache and neck pain due to cervicocerebral artery dissection (CAD).MethodsA total of 146 consecutive patients with CAD in Zhengzhou, China (2010–2017) were observed and registered prospectively. There were 60 (60/146) cases who complained of headache and neck pain, and we analyzed the characteristics of pain according to their clinical features. For the 130 (130/146) patients with complete clinical laboratory data, they were divided into two groups according to pain, and the relative factors of pain were analyzed.ResultsThe headache and neck pain in 60 CAD patients was mostly acute onset (98.3%), 70.6% (12/17) of patients with anterior circulation dissection and 88.4% (38/43) of patients with posterior circulation dissection complained of moderate to severe pain. 41.2% (7/17) of patients with anterior circulation dissection had temporal pain, while 46.5% (20/43) of the patients with posterior circulation dissection had occipital pain. There were 23.5% (4/17) and 32.6% (14/43) of patients with anterior and posterior circulation dissection complained of throbbing pain, respectively, 23.5% (4/17) and 20.9% (9/43) of patients with anterior and posterior circulation dissection complained of pulsating pain. The pain could occur in the ipsilateral (40.0%), bilateral (52.7%), or contralateral (7.3%) sites of the dissection. In the 130 patients, there were 56 cases (43.1%) in the pain group, and 74 cases (56.9%) in the non-pain group. Multivariate logistic regression analysis showed that female gender (OR 4.01, 95% CI 1.63–9.85, P = 0.002), posterior circulation (OR 3.18, 95% CI 1.39–7.28, P = 0.006), history of headache (OR 4.72, 95% CI 1.08–20.52, P = 0.039), and low-density lipoprotein less than 1.8 mmol/L (OR 2.90, 95% CI 1.15–7.34, P = 0.025) were risk factors of the occurrence of the pain related to CAD.ConclusionThe headache and neck pain caused by CAD is a moderate to severe pain occurring suddenly. The pain nature may be diverse but mostly like throbbing and pulsating. When the dissected artery is located in the posterior circulation, the pain is mostly in the occipital region, and mostly in the temporal region when the dissected artery is located in the anterior circulation. The pain can occur in ipsilateral, bilateral, or contralateral of the dissection. In addition, several factors might contribute to the occurrence of headache and neck pain.

Post-dural puncture headache (PDPH) is the most common complication of lumbar puncture. Aminophylline has been reported to be effective in the prevention of PDPH in some clinical studies, but its efficacy for the treatment of PDPH has been unproven. To evaluate the efficacy and safety of an intravenous (IV) injection of aminophylline on PDPH. The study was a multicenter, open-label study to assess the effectiveness and safety of aminophylline on PDPH. The First Affiliated Hospital of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, and Henan Province Hospital of Traditional Chinese Medicine. Thirty-two PDPH patients received an IV injection of aminophylline. The primary and secondary endpoints were the degree of headache and the patient's overall response to the treatment, respectively. Treatment safety was evaluated based on the occurrence of adverse reactions. Thirty-one patients completed the study. Before the initial aminophylline administration, the visual analog scale (VAS) score was 7.72 ± 1.65. The VAS scores at 30 minutes, one hour, 8 hours, one day, and 2 days post-treatment were 4.84 ± 2.53, 3.53 ± 2.06, 2.38 ± 1.96, 1.44 ± 1.87, and 0.81 ± 1.79, respectively, and were statistically significantly different (P < 0.05) compared with those before treatment. More than 50% (17/32) of the patients reported that they were \"very much improved\" or \"much improved\" 30 minutes after the initial treatment, increasing to 93.8% (30/32) at 2 days post-treatment. One patient experienced mild allergic reaction after treatment. Although this study had the largest sample size among current studies on treating PDPH with theophylline drugs, the sample size was still relatively small and the method employed was not compared with a placebo or other current clinical treatments for PDPH. An IV injection of aminophylline may be an effective and safe early-stage treatment for PDPH.

Botulinum neurotoxins (BoNTs) block the release of a series of neurotransmitters, which are pivotal for neuron action. Intrahippocampal administration of BoNTs inhibits glutamate release, protects neurons against cell death, and attenuates epileptic seizures. Compared with intrahippocampal administration, intranasal delivery is less invasive and more practical for chronic drug administration. To assess whether intranasal administration is feasible, we examined the role of botulinum neurotoxin A (BoNT/A) in hippocampal neuronal injury after status epilepticus (SE) induced by pilocarpine. Our data showed BoNT/A could bypass the blood–brain barrier (BBB) and entered the olfactory bulb and hippocampal neurons. In addition, SE could result in up-regulation of pro-apoptotic proteins (Caspase-3, Bax), down-regulation of anti-apoptotic protein Bcl-2 and neuronal death in hippocampus. BoNT/A could suppress the expression of Caspase-3 and Bax, attenuate the decrease of Bcl-2, and inhibit hippocampal neuron death induced by SE. Meanwhile, there was no significant difference in cognitive behavior between the BoNT/A-pretreated rats and normal rats. Thus, we provided a more convenient and less invasive route for taking advantage of BoNT/A in the field of anti-epilepsy.

Background BoNT-A is often used in the clinical treatment for movement disorders. In recent years, various clinical studies suggest that BoNT-A can effectively alleviate pain caused by trigeminal neuralgia (TN); however, its mechanism remains unclear. Methods In this study, we used a lab rat model for TN produced by chronic constriction injury of the infraorbital nerve (ION-CCI). Restrained rats were injected subcutaneously with BoNT-A into the whisker pad tissue (ipsilaterally to the nerve injury) 14 days after the ION-CCI. Allodynia was tested by Von Frey filaments and TRPs and cSNAP-25 were tested by western blot. Results Peripheral application of BoNT-A (3, 10 U/kg) significantly increased the pain threshold of ION-CCI rats. Rota-rod test showed that BoNT-A administration at doses tested did not significantly affect rat motor coordination. By probing for a specific marker for BoNT-A, cleaved synaptosomal-associated protein 25 (cSNAP-25), we found that peripheral application of BoNT-A (10 U/kg) affected brainstem Vc, which could be blocked by the axonal transport blocker colchicine. In addition, western blot analysis showed that in the Vc region of ION-CCI rats, the expression levels of TRPA1, TRPV1, TRPV2 and TRPM8 increased, whereas peripheral application of BoNT-A significantly lowered the high expression of TRPA1, TRPV1 and TRPV2, but not TRPM8 at 7 days after BoNT-A injection. Conclusions The finding of this study suggest that peripherally applied BoNT-A can produce antinociceptive effects in ION-CCI model. The underlying mechanisms may be BoNT-A acts on the Vc via axonal transport, inhibits the high expression of TRPA1, TRPV1 and TRPV2, and reduces central sensitization.