Alternations in the excitatory (e.g., glutamate) and central inhibitory (e.g., γ-aminobutyric acid, or GABA) neurotransmission plays a crucial role in the etiology and clinical manifestations of epilepsy. During prolonged seizures, the decrease in the activity of GABA-A receptors causes an increase in the activity of glutamate-related N-methyl-D-aspartate (NMDA) receptors. A combination of different neurotransmitters and cytosolic proteins maintain the excitatory activity caused by the stimulation of NMDAR within physiological limits. However, during epilepsy, NMDAR stimulation escapes this control mechanism and causes the generation of seizures. The enhanced stimulation of NMDAR has been attributed to some G protein-coupled receptors (GPCRs), which include serotonin 5HT2A/C receptors. Moreover, the physical coupling and uncoupling of GPCRs with NMDARs are supported by histidine triad nucleotide-binding protein 1 (HINT1) and sigma receptor type 1 (σ1R). Previous studies have indicated that fenfluramine can be used in the treatment of epilepsy because it targets the 5HT2 receptor family in the brain. However, the exact underlying mechanism of the anticonvulsant activity of fenfluramine remains unknown. Although recent studies have indicated that some σ1R ligands ameliorate acute prolonged seizures (ak.a. status epilepticus) and antagonize electrical tonic convulsions in mice, the role of σ1Rs in the pathophysiology of epilepsy and their therapeutic potential as anticonvulsive agents have not been fully established.
Spanish researchers: María Rodríguez-Muñoz, Pilar Sánchez-Blázquez and Javier Garzón from the Department of Translational Neurosciences at Cajal Institute demonstrated that fenfluramine interacts directly with the activity of 5HT2Rs and σ1Rs, and indirectly with the activity of GPCRs to restrain the activity of NMDARs. The work is published in the peer-reviewed journal, Oncotarget.
The authors observed that fenfluramine and its metabolite (norfenfluramine) disrupted and displayed a dose-dependent capacity to diminish the association between NR1 and σ1R proteins while fenfluramine, norfenfluramine, and S1RA increased the calcium-dependent association of CaM (a negative regulator of NMDAR). However, these effects were diminished by the σ1R agonist PPCC.
Furthermore, they also observed that S1RA treatment reduced the incidence of NMDA-induced wild running and clonic convulsions (by approximately 50%) and protected the mice from NMDA-provoked death. Tonic seizures were seen in only 20% of the mice. On the other hand, fenfluramine and norfenfluramine reduced the appearance of most NMDA-induced signs (i.e. compulsive rearing, wild running, clonic convulsions, and tonic seizures) and protected the mice from NMDA-provoked death. Fenfluramine was more effective at reducing rearing in mice, while norfenfluramine abolished clonic convulsions and tonic seizures in mice. PPCC impaired the capacity of S1RA, fenfluramine, and norfenfluramine to diminish NMDA-induced signs while serotonin 5HT2AR antagonist (4F 4PP) antagonized the effects of fenfluramine and norfenfluramine.
This novel study by Cajal Institute scientists provides compelling evidence that fenfluramine via its mixed actitity at serotonin 5HT2A and type 1 sigma receptors diminishes the incidence and extent of seizures promoted by the overactivity of NMDARs. These findings will advance further studies on ways to circumvent the negative side effects of direct NMDAR antagonists and the use of mixed drugs to reduce the severity of the convulsing syndrome.
Rodríguez-Muñoz, M., Sánchez-Blázquez, P., and Garzón, J. Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors, Oncotarget 9:34 (2018) 23373-23389