P2X7 receptor antagonism by AZ10606120 significantly reduced in vitro tumour growth in human glioblastoma.

Glioblastomas are highly aggressive and deadly brain tumours, with a median survival time of 14-18 months post-diagnosis. Current treatment modalities are limited and only modestly increase survival time. Effective therapeutic alternatives are urgently needed. The purinergic P2X7 receptor (P2X7R) is activated within the glioblastoma microenvironment and evidence suggests it contributes to tumour growth. Studies have implicated P2X7R involvement in a range of neoplasms, including glioblastomas, although the roles of P2X7R in the tumour milieu remain unclear. Here, we report a trophic, tumour-promoting role of P2X7R activation in both patient-derived primary glioblastoma cultures and the U251 human glioblastoma cell line, and demonstrate its inhibition reduces tumour growth in vitro. Primary glioblastoma and U251 cell cultures were treated with the specific P2X7R antagonist, AZ10606120 (AZ), for 72 h. The effects of AZ treatment were also compared to cells treated with the current first-line chemotherapeutic drug, temozolomide (TMZ), and a combination of both AZ and TMZ. P2X7R antagonism by AZ significantly depleted glioblastoma cell numbers compared to untreated cells, in both primary glioblastoma and U251 cultures. Notably, AZ treatment was more effective at tumour cell killing than TMZ. No synergistic effect between AZ and TMZ was observed. AZ treatment also significantly increased lactate dehydrogenase release in primary glioblastoma cultures, suggesting AZ-induced cellular cytotoxicity. Our results reveal a trophic role of P2X7R in glioblastoma. Importantly, these data highlight the potential for P2X7R inhibition as a novel and effective alternative therapeutic approach for patients with lethal glioblastomas.

Acquired cardiac channelopathies in epilepsy: Evidence, mechanisms, and clinical significance.

There is growing evidence that cardiac dysfunction in patients with chronic epilepsy could play a pathogenic role in sudden unexpected death in epilepsy (SUDEP). Recent animal studies have revealed that epilepsy secondarily alters the expression of cardiac ion channels alongside abnormal cardiac electrophysiology and remodeling. These molecular findings represent novel evidence for an acquired cardiac channelopathy in epilepsy, distinct from inherited ion channels mutations associated with cardiocerebral phenotypes. Specifically, seizure activity has been shown to alter the messenger RNA (mRNA) and protein expression of voltage-gated sodium channels (Nav 1.1, Nav 1.5), voltage-gated potassium channels (Kv 4.2, Kv 4.3), sodium-calcium exchangers (NCX1), and nonspecific cation-conducting channels (HCN2, HCN4). The pathophysiology may involve autonomic dysfunction and structural cardiac disease, as both are independently associated with epilepsy and ion channel dysregulation. Indeed, in vivo and in vitro studies of cardiac pathology reveal a complex network of signaling pathways and transcription factors regulating ion channel expression in the setting of sympathetic overactivity, cardiac failure, and hypertrophy. Other mechanisms such as circulating inflammatory mediators or exogenous effects of antiepileptic medications lack evidence. Moreover, an acquired cardiac channelopathy may underlie the electrophysiologic cardiac abnormalities seen in chronic epilepsy, potentially contributing to the increased risk of malignant arrhythmias and sudden death. Therefore, further investigation is necessary to establish whether cardiac ion channel dysregulation similarly occurs in patients with epilepsy, and to characterize any pathogenic relationship with SUDEP.

MRI-identified pathology in adults with new-onset seizures.

OBJECTIVE: To determine the frequency and nature of potentially epileptogenic lesions on MRI in adults with new-onset seizures. METHODS: We prospectively studied a consecutive series of 993 patients (597 males [61%]; mean [SD] age: 42.2 [18.8] years, range 14.3-94.3 years) who presented to an adult First Seizure Clinic over a 10-year period. The MRI scans, performed clinically on 3- and 1.5-tesla scanners, were reviewed for their diagnostic yield, nature of abnormalities, and their association with abnormal electrical activity on EEG. RESULTS: MRI scans were acquired in 764 patients (77%); potentially epileptogenic lesions were detected in 177 (23%). The frequency of potentially epileptogenic lesions was higher in patients who were diagnosed as having an epileptic seizure (28%) than in those with a nonepileptic event (8%) (p < 0.001), and highest in those who had focal-onset seizures (53%) (p < 0.001). The most common lesion type in patients with focal seizures was gliosis or encephalomalacia (49%). Other common lesion types were tumors (15%), cavernomas (9%), and mesial temporal sclerosis (9%). Abnormal MRI and EEG were concordant in 18% of patients, with EEG being normal in 55% of patients with epileptogenic lesions. CONCLUSIONS: MRI reveals potentially epileptogenic lesions in a minority of patients with a newly diagnosed seizure disorder. Lesions are most common in patients who have experienced focal seizures. The presence of a potentially epileptogenic MRI lesion did not influence the chance of having an abnormal EEG.