The Transient Receptor Potential Melastatin 7 (TRPM7) Inhibitors Suppress Seizure-Induced Neuron Death by Inhibiting Zinc Neurotoxicity.

Transient receptor potential melastatin 7 (TRPM7) is an ion channel that mediates monovalent cations out of cells, as well as the entry of divalent cations, such as zinc, magnesium, and calcium, into the cell. It has been reported that inhibitors of TRPM7 are neuroprotective in various neurological diseases. Previous studies in our lab suggested that seizure-induced neuronal death may be caused by the excessive release of vesicular zinc and the subsequent accumulation of zinc in the neurons. However, no studies have evaluated the effects of carvacrol and 2-aminoethoxydiphenyl borate (2-APB), both inhibitors of TRPM7, on the accumulation of intracellular zinc in dying neurons following seizure. Here, we investigated the therapeutic efficacy of carvacrol and 2-APB against pilocarpine-induced seizure. Carvacrol (50 mg/kg) was injected once per day for 3 or 7 days after seizure. 2-APB (2 mg/kg) was also injected once per day for 3 days after seizure. We found that inhibitors of TRPM7 reduced seizure-induced TRPM7 overexpression, intracellular zinc accumulation, and reactive oxygen species production. Moreover, there was a suppression of oxidative stress, glial activation, and the blood-brain barrier breakdown. In addition, inhibitors of TRPM7 remarkably decreased apoptotic neuron death following seizure. Taken together, the present study demonstrates that TRPM7-mediated zinc translocation is involved in neuron death after seizure. The present study suggests that inhibitors of TRPM7 may have high therapeutic potential to reduce seizure-induced neuron death.

Protective Effects of Protocatechuic Acid on Seizure-Induced Neuronal Death.

Protocatechuic acid (PCA) is a type of phenolic acid found in green tea and has been shown to have potent antioxidant and anti-inflammatory properties. However, the effect of PCA on pilocarpine seizure-induced neuronal death in the hippocampus has not been evaluated. In the present study, we investigated the potential therapeutic effects of PCA on seizure-induced brain injury. Epileptic seizure was induced by intraperitoneal (i.p.) injection of pilocarpine (25 mg/kg) in adult male rats, and PCA (30 mg/kg) was injected into the intraperitoneal space for three consecutive days after the seizure. Neuronal injury and oxidative stress were evaluated three days after a seizure. To confirm whether PCA increases neuronal survival and reduced oxidative injury in the hippocampus, we performed Fluoro-Jade-B (FJB) staining to detect neuronal death and 4-hydroxynonenal (4HNE) staining to detect oxidative stress after the seizure. In the present study, we found that, compared to the seizure vehicle-treated group, PCA administration reduced neuronal death and oxidative stress in the hippocampus. To verify whether a decrease of neuronal death by PCA treatment was due to reduced glutathione (GSH) concentration, we measured glutathione with N-ethylmaleimide (GS-NEM) levels in hippocampal neurons. A seizure-induced reduction in the hippocampal neuronal GSH concentration was preserved by PCA treatment. We also examined whether microglia activation was affected by the PCA treatment after a seizure, using CD11b staining. Here, we found that seizure-induced microglia activation was significantly reduced by the PCA treatment. Therefore, the present study demonstrates that PCA deserves further investigation as a therapeutic agent for reducing hippocampal neuronal death after epileptic seizures.

Effects of Protocatechuic Acid (PCA) on Global Cerebral Ischemia-Induced Hippocampal Neuronal Death.

Global cerebral ischemia (GCI) is one of the main causes of hippocampal neuronal death. Ischemic damage can be rescued by early blood reperfusion. However, under some circumstances reperfusion itself can trigger a cell death process that is initiated by the reintroduction of blood, followed by the production of superoxide, a blood⁻brain barrier (BBB) disruption and microglial activation. Protocatechuic acid (PCA) is a major metabolite of the antioxidant polyphenols, which have been discovered in green tea. PCA has been shown to have antioxidant effects on healthy cells and anti-proliferative effects on tumor cells. To test whether PCA can prevent ischemia-induced hippocampal neuronal death, rats were injected with PCA (30 mg/kg/day) per oral (p.o) for one week after global ischemia. To evaluate degenerating neurons, oxidative stress, microglial activation and BBB disruption, we performed Fluoro-Jade B (FJB), 4-hydroxynonenal (4HNE), CD11b, GFAP and IgG staining. In the present study, we found that PCA significantly decreased degenerating neuronal cell death, oxidative stress, microglial activation, astrocyte activation and BBB disruption compared with the vehicle-treated group after ischemia. In addition, an ischemia-induced reduction in glutathione (GSH) concentration in hippocampal neurons was recovered by PCA administration. Therefore, the administration of PCA may be further investigated as a promising tool for decreasing hippocampal neuronal death after global cerebral ischemia.

Inhibition of NADPH Oxidase Activation by Apocynin Rescues Seizure-Induced Reduction of Adult Hippocampal Neurogenesis.

Apocynin, also known as acetovanillone, is a natural organic compound structurally related to vanillin. Apocynin is known to be an inhibitor of NADPH (Nicotinamide adenine dinucleotide phosphate) oxidase activity and is highly effective in suppressing the production of superoxide. The neuroprotective effects of apocynin have been investigated in numerous brain injury settings, such as stroke, traumatic brain injury (TBI), and epilepsy. Our lab has demonstrated that TBI or seizure-induced oxidative injury and neuronal death were reduced by apocynin treatment. Several studies have also demonstrated that neuroblast production is transiently increased in the hippocampus after seizures. Here, we provide evidence confirming the hypothesis that long-term treatment with apocynin may enhance newly generated hippocampal neuronal survival by reduction of superoxide production after seizures. A seizure was induced by pilocarpine [(25 mg/kg intraperitoneal (i.p.)] injection. Apocynin was continuously injected for 4 weeks after seizures (once per day) into the intraperitoneal space. We evaluated neuronal nuclear antigen (NeuN), bromodeoxyuridine (BrdU), and doublecortin (DCX) immunostaining to determine whether treatment with apocynin increased neuronal survival and neurogenesis in the hippocampus after seizures. The present study indicates that long-term treatment of apocynin increased the number of NeuN⁺ and DCX⁺ cells in the hippocampus after seizures. Therefore, this study suggests that apocynin treatment increased neuronal survival and neuroblast production by reduction of hippocampal oxidative injury after seizures.

Are the anomalous vertebral arteries more hypoplastic?: retrospective linear mixed model approach.

BACKGROUND: Small or hypoplastic vertebral artery (VA) is one of the risk factor for posterior circulation stroke. We assess whether various types of VA anomaly contribute to its diameter. METHODS: We screened 238 patients who underwent neck CT and MR angiography within 1 month. A V1 anomaly was defined as the abnormal origin of the VA on a three-dimensional MR angiography and a V2 anomaly was defined as the VA not passing through the 6th cervical transverse foramen (TF) on an axial CT image. A linear mixed model was used to evaluate the determinants of VA size. RESULTS: Among participants, 24 (10.1%) subjects exhibited an anomalous VA and, of the 476 VAs examined, 11 (2.3%) had an aortic origin and 27 (5.7%) had an abnormal entrance into the C6 TF. Presence of the V1 anomaly was positively associated with the V2 anomaly (P for chi-square < 0.001) and a linear mixed model revealed that being male (0.2 mm larger, P = 0.015), having a right VA anomaly (0.3 mm smaller, P < 0.001), having a V1 anomaly (0.9 mm smaller, P < 0.001), and having a V2 anomaly (0.7 mm smaller, P < 0.001) were significant predictor of VA diameter. CONCLUSION: The diameters of VAs with an anomalous aortic origin or an abnormal entrance of the TF were significantly smaller than those of normal VAs. These findings suggest that anomalies of the VA detected in 3-dimensional CTA or MRA may be clues for vertebral artery hypoplasia.

Diverse Effects of an Acetylcholinesterase Inhibitor, Donepezil, on Hippocampal Neuronal Death after Pilocarpine-Induced Seizure.

Epileptic seizures are short episodes of abnormal brain electrical activity. Many survivors of severe epilepsy display delayed neuronal death and permanent cognitive impairment. Donepezil is an acetylcholinesterase inhibitor and is an effective treatment agent for Alzheimer's disease. However, the role of donepezil in seizure-induced hippocampal injury remains untested. Temporal lobe epilepsy (TLE) was induced by intraperitoneal injection of pilocarpine (25 mg/kg). Donepezil (2.5 mg/kg/day) was administered by gavage in three different settings: (1) pretreatment for three days before the seizure; (2) for one week immediately after the seizure; and (3) for three weeks from three weeks after the seizure. We found that donepezil showed mixed effects on seizure-induced brain injury, which were dependent on the treatment schedule. Pretreatment with donepezil aggravated neuronal death, oxidative injury, and microglia activation. Early treatment with donepezil for one week showed neither adverse nor beneficial effects; however, a treatment duration of three weeks starting three weeks after the seizure showed a significant reduction in neuronal death, oxidative injury, and microglia activation. In conclusion, donepezil has therapeutic effects when injected for three weeks after seizure activity subsides. Therefore, the present study suggests that the therapeutic use of donepezil for epilepsy patients requires a well-conceived strategy for administration.

Differences in cognitive function between patients with viral and alcoholic compensated liver cirrhosis.

As alcohol induces change in frontal cortex primarily involved in cognition, cognitive function may be different between viral and alcoholic liver cirrhosis (LC). This study aimed to determine the differences of cognitive function between viral and alcoholic compensated LC. From October 2011 to March 2013, 80 patients (viral: 37; alcohol: 43) with compensated LC were prospectively enrolled. Neuropsychological functions including attention, language, visuospatial, verbal memory, visual memory, and frontal/executive function were evaluated between two groups and compared with age-matched normal group (n = 1000). Cumulative incidence rate of overt hepatic encephalopathy (HE) was calculated. In the comparison with normal group, both two groups showed decreased memory function, frontal/executive function, and Korea-Mini Mental Status Examination. In the analysis of two groups, memory function by Verbal Learning Test (recognition: 20.1 ± 3.6 and 17.8 ± 4.8, p = 0.022), visuospatial function by Ray-Complex Figure Copy Test (recognition: 19.0 ± 2.6 and 17.3 ± 4.0, p = 0.043), frontal/executive function by Controlled Oral Ward Association (semantic: 17.1 ± 6.9 and 12.7 ± 6.9, p = 0.004), and the Korea-Mini Mental Status Examination (27.5 ± 1.9 and 26.2 ± 3.1, p = 0.03) showed low scores in alcoholic compensated LC patients. The 1-, 2-, and 3-year cumulative incidence rates of overt HE were 23%, 26%, and 26% and 33%, 43%, and 49% in the viral and alcoholic compensated LC group, respectively (p = 0.033). Impaired memory and frontal lobe executive functions and early development of overt HE were more common in patients with alcoholic LC. For patients with alcoholic LC, more integrated tests for early detection of minimal HE and intensive treatment should be considered to prevent overt HE.

Differences in central facilitation between episodic and chronic migraineurs in nociceptive-specific trigeminal pathways.

BACKGROUND: The trigeminal nociceptive system plays a pivotal role in the pathophysiology of migraines. The present study investigated whether there are differences between patients with episodic migraine (EM) and patients with chronic migraine (CM) in trigeminal pain processing at the brainstem and cortical levels using the nociceptive blink reflex (nBR) and pain-related evoked potentials (PREP). METHODS: This study assessed 68 female migraineurs (38 EM patients and 30 CM patients) and 40 age-matched controls using simultaneous recordings of nBR and PREP during the interictal period. RESULTS: In terms of the nBR, EM patients displayed significantly decreased latencies and larger amplitudes and area-under-the-curve (AUC) values for the R2 component, whereas CM patients showed significantly prolonged latencies and smaller amplitudes and AUC values for the R2 component (p < 0.05). In terms of PREP, both the EM and CM patients had decreased latencies (N1, P1), with larger amplitude compared with the controls (p < 0.05), which indicates facilitation at the cortical level. Additionally, the amplitude and AUC values of the R2 component exhibited a negative correlation, whereas the latency of the R2 component for the nBR showed a positive correlation, with the frequency of headaches in migraineurs (p < 0.01). CONCLUSIONS: In the present study, the facilitation in the trigeminal nociceptive pathway of the EM group suggests the occurrence of migraine-specific hyperexcitability. Additionally, the suppression of R2 at the brainstem level in the CM group may relate to impaired or dysfunctional descending pain modulation. These findings suggest that there are adaptive or maladaptive responses due to the chronification of migraine attacks.

Subclinical vestibular dysfunction in migraine patients: a preliminary study of ocular and rectified cervical vestibular evoked myogenic potentials.

BACKGROUND: Many studies have identified various vestibular symptoms and laboratory abnormalities in migraineurs. Although the vestibular tests may be abnormal, the changes may exist without vestibular symptoms. To date, vestibular-evoked myogenic potential (VEMP) has been the easiest and simplest test for measuring vestibular function in clinical practice. Cervical VEMP (cVEMP) represents a vestibulo-collic reflex, whereas ocular VEMP (oVEMP) reflects a vestibulo-ocular pathway. Therefore, we determined whether ocular and rectified cervical VEMPs differed in patients with migraine or tension type headache (TTH) and compared the results to controls with no accompanying vestibular symptoms. METHODS: The present study included 38 females with migraine without aura, 30 with episodic TTH, and 50 healthy controls without vestibular symptoms. oVEMP and cVEMP using a blood pressure manometer were recorded during a headache-free period. From the VEMP graphs, latency and amplitude parameters were analyzed, especially following EMG rectification in cVEMP. RESULTS: With respect to oVEMP, the migraine group exhibited significantly longer mean latencies of bilateral n1 and left p1 than the other groups (p < 0.05). Amplitudes of n1-p1 were lower than in other groups, but the difference did not reach statistical significance. In regards to cVEMP, p13 and n23 latencies and amplitudes after rectification did not differ significantly among groups. CONCLUSIONS: An abnormal interictal oVEMP profile was associated with subclinical vestibular dysfunction in migraineurs, suggesting pathology within the vestibulo-ocular reflex. oVEMP is a more reliable measure than cVEMP to evaluate vestibular function in migraineurs, although results from the two tests in patients with migraine are complementary.

Fulminant cerebral infarction of anterior and posterior cerebral circulation after ascending type of facial necrotizing fasciitis.

Necrotizing fasciitis is a soft tissue infection that is characterized by extensive necrosis of the subcutaneous fat, neurovascular structures, and fascia. Cerebral infarction after facial necrotizing fasciitis has been rarely reported. A 61-year-old woman with diabetes was admitted with painful swelling of her right cheek. One day later, she was stuporous and quadriplegic. A computed tomographic scan of her face revealed right facial infection in the periorbital soft tissue, parotid, buccal muscle, and maxillary sinusitis. A computed tomographic scan of the brain revealed cerebral infarction in the right hemisphere, left frontal area, and both cerebellum. Four days later, she died from cerebral edema and septic shock. Involvement of the cerebral vasculature, such as the carotid or vertebral artery by necrotizing fasciitis, can cause cerebral infarction. Facial necrotizing fasciitis should be treated early with surgical treatment and the appropriate antibiotic therapy.