The effect of P2X7 antagonism on subcortical spread of optogenetically-triggered cortical spreading depression and neuroinflammation.

Migraine is a neurological disorder characterized by episodes of severe headache. Cortical spreading depression (CSD), the electrophysiological equivalent of migraine aura, results in opening of pannexin 1 megachannels that release ATP and triggers parenchymal neuroinflammatory signaling cascade in the cortex. Migraine symptoms suggesting subcortical dysfunction bring subcortical spread of CSD under the light. Here, we investigated the role of purinergic P2X7 receptors on the subcortical spread of CSD and its consequent neuroinflammation using a potent and selective P2X7R antagonist, JNJ-47965567. P2X7R antagonism had no effect on the CSD threshold and characteristics but increased the latency to hypothalamic voltage deflection following CSD suggesting that ATP acts as a mediator in the subcortical spread. P2X7R antagonism also prevented cortical and subcortical neuronal activation following CSD, revealed by bilateral decrease in c-fos positive neuron count, and halted CSD-induced neuroinflammation revealed by decreased neuronal HMGB1 release and decreased nuclear translocation of NF-kappa B-p65 in astrocytes. In conclusion, our data suggest that P2X7R plays a role in CSD-induced neuroinflammation, subcortical spread of CSD and CSD-induced neuronal activation hence can be a potential target.

Treatment of COVID-19 Vaccine Resistant Migraine Attack with CGRP Monoclonal Antibody: A Case Report.

Many researches have shown that coronavirus infection can lead to neurological symptoms. The most common symptom is headache. Calcitonin gene-related peptide (CGRP), which has an important role in the pathophysiology of migraine, may have an active role in persistent headaches after COVID, due to the structural similarity between the CGRP receptor and the SARS-CoV-2 spike protein. In this case report, the effect of the anti-CGRP monoclonal antibody on the migraine attack occurring after COVID-19 m-RNA vaccine will be discussed. A 55-year-old female patient who is followed up with a diagnosis of chronic migraine, had severe and throbbing headache that started after the COVID-19 m-RNA vaccine. After galcanezumab (CGRP monoclonal antibody - CGRP mAb) was started in the patient whose complaints did not regress despite the adjustment of the current drug doses, clinically significant improvement was observed in her complaints after the first dose and it was planned to continue with 120 mg CGRP mAb per month in her follow-ups.

Protective Effects of Infliximab Against Kanamycin-Induced Ototoxicity in Rats.

HYPOTHESIS: To examine the protective effects of infliximab (INF) against kanamycin (KM)-induced hearing loss. BACKGROUND: Tumor necrosis factor α blockers can reduce cellular inflammatory reactions and decrease cell death. METHODS: Thirty-six rats with normal hearing were randomly divided into six groups. The first group was injected with 400 mg/kg KM intramuscularly (IM), the second group with 7 mg/kg INF intraperitoneally (IP) and 400 mg/kg KM IM, the third group with 7 mg/kg INF IP and 200 mg/kg KM IM, and the fourth group with 1 mg/kg 6-methylprednisolone (MP) IP and 400 mg/kg KM IM. Group 5 was injected with 1 mg/kg MP IP and 200 mg/kg KM IM, and group 6 with saline IP once. Auditory brain-stem response (ABR) for hearing thresholds was performed on days 7 and 14. From the frozen sections of the cochlea, the area of the stria vascularis, the number of neurons in the spiral ganglion, the fluorescence intensity of hair cells (FIHC), postsynaptic density (PSD), and presynaptic ribbons (PSRs) were calculated. RESULTS: The KM-induced increase in hearing thresholds was detected on the 14th day. Hearing was only preserved in the group treated with INF after low-dose KM exposure but not in the groups that received high-dose KM. The FIHC, excitatory PSD, and PSR were preserved only in the INF-treated group after half-dose KM exposure. In MP groups, FIHC, excitatory PSD, and PSR were significantly lower than in the control group. CONCLUSIONS: Our results support that tumor necrosis factor-based inflammation may play a role in the ototoxicity mechanism.

Impact of Autoimmune Demyelinating Brain Disease Sera on Pericyte Survival.

INTRODUCTION: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by demyelination and brain pericyte dysfunction might be involved in MS pathogenesis Our aim was to evaluate whether the factors in serum affect pericyte survival. METHOD: C57BL/6 female mice were immunized with myelin oligodendrocyte glycoprotein (MOG) to induce experimental autoimmune encephalomyelitis (EAE). To confirm the animal model, the sera level of anti-MOG antibody in mice and platelet-derived growth factor-BB (PDGF-BB) in patients was measured by ELISA. Human brain vascular pericytes (HBVP) cell lines were incubated with sera of EAE mice and primer progressive MS (PPMS), seconder progressive MS (SPMS) and relapsing-remitting MS (RRMS) patients. The viability of HBVP is measured with Annexin V-FITC/propidium iodide staining with flow cytometry. RESULTS: Annexin V-FITC/propidium iodide staining with flow cytometry showed increased ratios of early apoptosis and decreased survival following incubation with sera of EAE and progressive MS. Levels of platelet-derived growth factor-BB were identical in serum and cerebrospinal fluids of patients with different forms of MS. CONCLUSION: Our results suggest that serum factors might contribute to progressive MS pathogenesis via pericyte dysfunction.

A multidisciplinary clinical approach to facioscapulohumeral muscular dystrophy.

BACKGROUND AND PURPOSE: Impaired shoulder function is the most disabling problem for daily life of Fascioscapulohumeral muscular dystrophy (FSHD) patients. Scapulothoracic arthrodesis can give a high impact to the functionality of patients. Here we report our experience with scapulothoracic arthrodesis and spinal stenosis surgery in FSHD patients. METHODS: 32 FSHD patients were collected between 2015-2016. Demographical and clinical features were documented. All the patients were neurologically examined. The Medical Research Council (MRC) and the FSHD evaluation scale was used to assess muscle involvement1. Scapulothoracic arthrodesis and spinal stenosis surgeries were performed in eligible patients. RESULTS: There were 16 male and 16 female (mean age 34.4 years; range 12-73) patients. 6 shoulders of 4 patients aged between 2132 years underwent scapulothoracic arthrodesis (two bilateral, one left and one right sided). Only one 63 years old female patient with severe hyperlordosis had spinal fusion surgery. All of the patients undergoing these corrective surgeries have better functionality in daily life, as well as superior shoulder elevation. CONCLUSION: Until the emergence and clinical use of novel therapeutics, surgical interventions are indicated in carefully selected patients with FSHD to improve arm movements, the posture and the quality of life of patients in general. Scapulothorosic arthrodesis is a management with good clinical results and patient satisfaction. In selected cases other corrective orthopedic surgeries like spinal fusion may also be considered.

Is the cell death in mesial temporal sclerosis apoptotic?

PURPOSE: Mesial temporal sclerosis (MTS) is characterized by neuronal loss in the hippocampus. Studies on experimental models and patients with intractable epilepsy suggest that apoptosis may be involved in neuronal death induced by recurrent seizures. METHODS: We searched evidence for apoptotic cell death in temporal lobes resected from drug-resistant epilepsy patients with MTS by using the terminal deoxynucleotidyl transferase (TdT) and digoxigenin-11-dUTP (TUNEL) method and immunohistochemistry for Bcl-2, Bax, and caspase-cleaved actin fragment, fractin. The temporal lobe specimens were obtained from 15 patients (six women and nine men; mean age, 29 +/- 8 years). RESULTS: Unlike that in normal adult brain, we observed Bcl-2 immunoreactivity in some of the remaining neurons dispersed throughout the hippocampus proper as well as in most of the reactive astroglia. Bax immunopositivity was increased in almost all neurons. Fractin immunostaining, an indicator of caspase activity, was detected in approximately 10% of these neurons. Despite increased Bax expression and activation of caspases, we could not find evidence for DNA fragmentation by TUNEL staining. We also could not detect typical apoptotic changes in nuclear morphology by Hoechst-33258 or hematoxylin counterstaining. CONCLUSIONS: These data suggest that either apoptosis is not involved in cell loss in MTS, or a very slow rate of cell demise may have precluded detecting TUNEL-positive neurons dying through apoptosis. Increased Bax expression and activation of caspases support the latter possibility.