Drugs acting at TRPM7 channels inhibit seizure-like activity.

Transient receptor potential cation subfamily M7 (TRPM7) channels are ion channels permeable to divalent cations. They are abundantly expressed with particularly high expression in the brain. Previous studies have highlighted the importance of TRPM7 channels in brain diseases such as stroke and traumatic brain injury, yet evidence for a role in seizures and epilepsy is lacking. Here, we show that carvacrol, a food additive that inhibits TRPM7 channels, and waixenicin A, a novel selective and potent TRPM7 inhibitor, completely suppressed seizure-like activity in rodent hippocampal-entorhinal brain slices exposed to pentylenetetrazole or low magnesium. These findings support inhibition of TRPM7 channels as a novel target for antiseizure medications.

Carvacrol after status epilepticus (SE) prevents recurrent SE, early seizures, cell death, and cognitive decline.

OBJECTIVE: Carvacrol is a naturally occurring monoterpenic phenol that has been suggested to have an action at transient receptor potential cation subfamily M7 (TRPM7) channels, γ-aminobutyric acid (GABAA receptors, and sodium channels, and has been shown to be antiinflammatory. Carvacrol is neuroprotective in models of cerebral ischemia in vivo and in vitro, probably through its action at TRPM7 channels. We therefore aimed to determine the effect of carvacrol on status epilepticus (SE), chronic epilepsy, cell death, and post-SE cognitive decline. METHODS: We performed long-term, continuous wireless electroencephalography (EEG) monitoring in vivo in rats who underwent perforant path stimulation (PPS) to induce SE and were then randomized to treatment with carvacrol or saline. We also evaluated TRPM7 receptor expression and quantified seizure-induced cell death. The alternating T-maze paradigm was used to assess memory function. RESULTS: Immunostaining showed that TRPM7 channels are widely expressed in neurons within the hippocampus. We found that carvacrol inhibited recurrent SE and early seizures in vivo, but had no detectable effect in the hippocampus on paired-pulse inhibition or the fiber volley, indicating that it was not acting through sodium channel inhibition or GABA receptors. Although the development and severity of chronic epilepsy were not altered by carvacrol, cognitive decline was significantly improved in animals treated with carvacrol. In keeping with preserved memory functions in animals treated with carvacrol, carvacrol had a protective effect against SE-induced cell death in CA1 and hilus, the hippocampal regions most affected by cell loss in the PPS epilepsy model. SIGNIFICANCE: Carvacrol, a naturally occurring inhibitor of TRPM7 channels, is a novel, promising treatment to prevent early recurrence of SE, SE-related neuronal damage, and cognitive decline.

Predictors for being offered epilepsy surgery: 5-year experience of a tertiary referral centre.

OBJECTIVES: To define factors that predict whether patients with pharmacoresistant focal epilepsy are offered epilepsy surgery (including invasive EEG) and the main reasons for not proceeding with these after non-invasive presurgical evaluation. METHODS: We retrospectively analysed data from 612 consecutive patients with focal epilepsy admitted to a video-EEG Telemetry Unit for presurgical evaluation, and used a multivariate logistic regression model to assess the predictive value of factors for being offered potentially curative surgery. RESULTS: In the multivariate analysis, bilateral lesions on MRI (OR: 0.10; 95% CI 0.03 to 0.24), no lesion (OR: 0.33; 95% CI 0.22 to 0.49) or extratemporal lobe epilepsy (OR: 0.30; 95% CI 0.20 to 0.45) were the only factors that significantly reduced the probability of being offered surgery. 32% of patients who were offered epilepsy surgery decided against proceeding. CONCLUSIONS: There was a low chance (<10%) of being offered surgery if there were bilateral lesions on MRI and extratemporal lobe epilepsy. Patients should be given advice on the risk/benefit ratio and of realistic outcomes of epilepsy surgery; this may help reduce the number of patients who refuse surgery after comprehensive workup.

Loss of rapid eye movement sleep atonia in patients with REM sleep behavioral disorder, narcolepsy, and isolated loss of REM atonia.

STUDY OBJECTIVES: To compare the amounts of REM sleep without atonia (RSWA) between patients with REM sleep behavior disorder (RBD), "isolated loss of REM atonia," narcolepsy, and control subjects and determine if there were threshold values for the amount of RSWA that differentiate each group from controls. METHODS: Retrospective analyses of polysomnography (PSG) records were used employing strict quantitative criteria for the measurement of phasic and tonic EMG activity during REM sleep. The PSG recordings of 47 individuals were analyzed (RBD 16, isolated loss of REM atonia 11, narcolepsy 10, control 10). RESULTS: Patients with the diagnosis of isolated loss of REM atonia had significantly lower levels of EMG activity during REM sleep than those with RBD but higher than control subjects. RSWA was higher in narcolepsy than in loss of REM atonia but lower than for RBD patients. Receiver operating characteristic (ROC) curves provided threshold values with high specificity and sensitivity in all patient groups with a cutoff value ≥ 1.22% (100% correctly classified) for phasic and ≥ 3.17% for tonic (92% correctly classified) EMG activity in RBD. CONCLUSION: Quantification of REM sleep EMG activity can successfully differentiate RBD and isolated loss of REM atonia patients from controls. The consistently increased amount of RSWA in patients with narcolepsy indicates that this can be an additional marker for a diagnosis of narcolepsy. Longitudinal studies of patients with isolated loss of REM atonia are needed to evaluate if these patients are at risk of developing RBD or neurodegenerative disorders.