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Title: The role of Transient Receptor Potential Melastanin 7 (TRPM7) channels in epilepsy
Author: Khalil, A.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Drug-resistance occurs in about 30% of patients with epilepsy and is associated with increased mortality and morbidity and cognitive decline. Furthermore, present AEDs treat the symptom (seizures) but do not modify the disease or associated cognitive comorbidities and do not prevent the development of epilepsy following brain injury. Transient receptor potential melastanin 7 (TRPM7) is a ubiquitous, stress-activated channel, that plays essential roles in cell viability and Mg2+ homeostasis, and opening of the channel depolarises neurons. Inhibiting TRPM7 channels is neuroprotective in brain ischemia. Conditions that activate the channel, such as low intracellular Mg2+ concentrations, oxidative stress, and decreased intracellular pH occur during seizure activity. This thesis aimed to assess the role of blocking TRPM7 channel in preventing: 1) seizure occurrence, 2) seizure induced cell death, 3) the development of epilepsy after brain damage induced by status epilepticus (SE) and 4) cognitive comorbidity in epilepsy. The low Mg2+ and pentylenetetrazol (PTZ) in vitro seizure models were used in entorhinal-hippocampal slices to assess the effect of TRPM7 inhibitors carvacrol and Waxiencin A (a recent more specific inhibitor) on seizure-like activity. The perforant path stimulation (PPS) model of epilepsy was used to investigate the effect of carvacrol on status epilepticus (SE), chronic epilepsy and memory dysfunction in epilepsy in vivo. TRPM7 inhibitors abolished (carvacrol) or significantly reduced (Waxiencin A) seizure-like activity in vitro indicating that TRPM7 channels contribute to seizure generation. Status epilepticus resulted in cell loss in CA1 area and hilus in the PPS model of epilepsy, and this was rescued by treatment with carvacrol, suggesting that TRPM7 channels contribute to status epilepticus induced cell death. Blocking TRPM7 channels in vivo prevented the occurrence of recurrent SE and early seizures following induced SE but did not affect chronic seizures. Lastly, TRPM7 channel inhibition by carvacrol significantly prevented memory impairment as measured by rewarded T-maze alternation in chronic epilepsy. These findings suggest that in vitro seizure-like activity and the sequelae of status epilepticus and chronic epilepsy such as neuronal death and memory dysfunction can be effectively treated by blocking TRPM7 channels.
Supervisor: Walker, Matthew Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available