The Effects of Gabapentin on Epileptic Seizures A Computational Model

The Effects of Gabapentin on Epileptic Seizures: A Computational Model Results Introduction Epilepsy is a neurological disorder that causes repetitive episodes of sensory disturbance, often manifested as epileptic seizures, which occur due to electrical misfires in the brain. Current therapeutics have been shown to be harmful for long term use: Sedatives, used to stop epileptic seizures tend to cause breathing difficulties in patients. Some anticonvulsant, sedative drugs can cause seizures in patients with pre-existing epilepsy. Administering gabapentin, an alternative anticonvulsant and nerve pain medication, has shown to be a more effective method of treatment for epileptic seizures. Start of seizure activity Fig. 1 Molecular structure of gabapentin. Gabapentin is a drug that interacts with cortical neurons at auxiliary subunits of voltage gated calcium channels, which control synaptic transmission in excitable neurons, in order to modulate certain types of Ca2+ current. Mechanism of action of gabapentin: Increases GABA responses at non-synaptic sites in neuronal tissues Reduces the release of mono-amine neurotransmitters by binding to NMDA receptors on the postsynaptic terminal The goal of our study was to determine the conditions under which Gabapentin has the greatest potential to suppress epileptic seizures through its interactions with voltage-gated calcium ion channels. __________________ Fig. 2 Gabapentin binds to receptors to reduce neurotransmitter release. Methods 2 Adapted a Python NEURON model that simulates seizures in the CA3 region of the hippocampus: Simulates CA3 neurons consisting of: Pyramidal cells Basket cells Oriens-lacunosum moleculare (OLM) cells Rendered epileptic when dendritic inhibition to pyramidal cells is impaired due to the dysfunction of OLM interneurons. After standardizing the baseline activity (theta-modulated gamma oscillations), systematic changes are made in the connectivitions between the neurons in order to compensate for the impairment of dendritic inhibition. Utilizes GABA, AMPA, and NMDA receptors and both the HCN1 and HCN2 genes. This model analyzes the activity patterns, oscillations, and brain rhythms when the network becomes epileptic. After running, simulations will generate 3 graphs: Raster plot Local field potential (LFP) graph Power Spectrum Density Implementing Gabapentin: Voltage gated calcium channels are added to the soma and dendrites of excitatory pyramidal cells. Fig. 3 Voltage gated calcium channels through which gabapentin acts (Dolphin, 2018, "Voltage-gated calcium channel α2δ subunits") A gabapentin variable is created to assign various dosages of gabapentin on a scale from 0 to 1. When the gabapentin dose is increased, the calcium channel conductance is reduced in the soma and dendrites of pyramidal cells. 3 simulations were run at 3 gabapentin dose levels: No dose, medial dose, and maximum dose Data is graphed using matplotlib Conclusion Each simulation displays three graphs: Local Field Potential Graphs electrical activity in the brain in the CA3 region of the hippocampus Plot shows voltage (mV) vs. time (ms) Chaotic spiking activity is characteristic of seizure behavior Raster Plot Displays the spiking activity of the group of neurons over time Seizure activity is characterized by frequent and irregular spiking Regular spiking represents healthy baseline brain activity Power Spectrum Density Uses Fast Fourier Transforms to display dominant frequencies in firing activity 0% gabapentin displays beta oscillations with high density at 32 Hz and gamma oscillations at 63 Hz. 100% gabapentin dose reduces beta and gamma oscillations Based on our analysis, a maximum dosage of gabapentin was optimal in suppressing the seizure. However, a small dosage had a minimal effect on the seizures. Our results support the current hypothesis that gabapentin is a viable anticonvulsant to treat epileptic seizures as long as it is supplied in appropriate doses. Our model has the potential to assist future studies of epileptic seizures by finding dosages of gabapentin that will result in the greatest decrease of uncontrollable epileptic brain activity. Future clinical trials are necessary to determine the adequate dosage and legitimacy of the drug in epilepsy patients. Fig. 4 The process of epilepsy in the human brain that can be treated through a real life application of our computational model. __________________ (Cleveland Clinic, 2022) __________________