Medicine (RMH) - Theses
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ItemTranslational investigations of the intersection between Alzheimer’s disease and epilepsy: mechanistic insights and treatment opportunities( 2019)Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive deficits compromising patients’ execution of daily activities. The incidence of unprovoked seizures has been reported to be higher in AD compared to healthy age matched population and is considered a risk factor for the development of acquired epilepsy. Abnormal electrical activity has also been correlated with increased cognitive decline in these patients and may be associated with a faster progression of AD symptoms. Thus, understanding how seizures develop in AD and how to treat them would be of extreme relevance for developing more effective therapies. The work presented in this thesis used a bidirectional approach to investigate the relationship between epilepsy and AD and potential treatment options. First, three antiepileptic drugs were assessed in their ability to delay the development of acquired epileptogenesis in the Tg2576 mice. These widely studied AD mice overexpress the human form of the amyloid precursor protein (APP) with a mutation that results in increased deposition of amyloid plaques with age. The amygdala kindling model was used to induce epileptogenesis and previous studies have shown that these mice have increased susceptibility to kindling induced seizures. The antiepileptic drugs brivaracetam (BRV), levetiracetam (LEV) and lacosamide (LAC) were administered via subcutaneously implanted osmotic pumps. BRV and LEV act through ligand binding to the SV2A synaptic vesicle protein and LAC through Na+ channels. After 28 days of continuous treatment with either one of the drugs or vehicle (VEH) animals were submitted to daily electrical stimulations, also under treatment, and the only drug able to slow down the epileptogenic process was BRV. Therefore, in the second study, the effect of BRV was further investigated. Mice were then pre-treated for 28 days, but pumps were removed, and drug allowed to wash-out for one week before kindling. BRV demonstrated a long-lasting effect and treated Tg2576 mice required significantly more stimulations to experience the first class 5 seizure. Investigations of the potential mechanisms underlying this effect revealed that BRV is not acting through changes in the expression levels of APP protein or SV2 mRNA. Lastly, with an approach in the opposite direction, a histopathological evaluation of resected tissue from patients with temporal lobe epilepsy (TLE) aimed at correlating the cognitive deficits often found in these patients with the presence of AD lesion hallmarks (tau and amyloid pathology). However, no significant tau deposition was found and although amyloid plaques were present in a higher proportion of patients compared to other similar studies, there was no strong evidence to suggest it is the mechanism responsible for cognitive impairments. In conclusion, network treatment strategies, such as antiepileptic drugs, could be useful in the treatment of seizures in AD, and in this study a potential antiepileptogenic effect was demonstrated for BRV in an AD-acquired epilepsy model. We have also shown that amyloid and tau pathology may not be the main underlying cause of cognitive deficits in TLE, but understanding these mechanisms might also advance our understanding of cognitive decline in AD.
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ItemGenetic and molecular determinants of acquired and genetic epilepsy( 2016)Introduction: Despite the differences in the pathophysiological mechanisms and clinical features of both genetic and acquired epilepsies, dysfunction of both voltage- and ligand-gated ion channels have been highlighted as major contributors of the epileptic phenotype. In this thesis, the molecular mechanism by which T-type Ca2+ channels, AMPAR and TARPs lead to the development of epilepsy was evaluated. In addition, whole genome sequencing was utilised to identify novel candidate genes that could play a role in the epilepsy phenotype. Results: Anti-epileptogenic effects of selective blocking of T-type calcium channels in models of acquired epilepsy. The anti-epileptogenic effects of Z944, a novel, potent and highly selective T-type Ca2+ was used in the amygdala kindling and post-status epilepticus (SE) model. In the amygdala kindling model, Z944 a novel, potent and highly selective T-type Ca2+, did not suppress seizures in fully kindled rats. However, treatment with Z944 delayed de progression of kindling. In the post-SE model, treatment with Z944 after SE massively reduced the number of spontaneous seizures in comparison to vehicle and levetiracetam treated animals. Moreover, treatment with Z944 showed a strong comorbidity modifier effect in depressive like behaviour and may improve cognition after SE. Effects of the T-type calcium channel CaV3.2 R1584P mutation on seizure susceptibility in congenic rats. The CaV3.2 R1584P mutation was not enough to cause absence seizures in a seizure resistant background in the congenic animals but may be associated with the anxiety phenotype. However, the genetic background of the NEC congenic might contain genes that may suppress the pro-epileptic effect of the R1584P mutation. Role of AMPAR and TARPs in the pathogenesis of genetic generalised epilepsy and acquired epilepsy. The results of this chapter indicate a temporal association between the increased TARPs, Stargazin, γ3, γ4, γ5 and γ8, mRNA expression and the development of absence seizures in GAERS. In the post-SE epilepticus model, there was a significant reduction in mRNA expression in the TARPs γ3 and γ8 in the hippocampus 13 weeks after SE. Whole genome sequencing the GAERS and NEC rat strains. TThrough the proposed screen construct variants were identified in high-seizing F2 rats in the following genes; Cacna1h which codes for the CaV3.2 T-type Ca2+ channel, and F1LVI7_RAT and LOC300024. Similarly, non-seizing F2 rats are heterozygous for the mutations in RGD1308133, D3ZPQ1_RAT, Mkl and BiK. In the NEC and F2 non-seizing variants found in Abat, Cyp11b3 and Cyp11b2. Moreover, the flexibility of this method means that it can be applicable with other models of genetic and acquired epilepsies. Conclusions: Here is shown that blocking T-type Ca2+ channels with Z944 has encouraging positive preclinical evidence for disease-modifying in epileptogenesis and in epilepsy behavioural comorbidities that may be possible to translate to a clinical trial. Moreover, the analysis of T-type Ca2+ channels, AMPAR, TARPs and the discovery of novel potential molecular targets using whole genome sequencing uncovers overlap among genetic and acquired epilepsy. Importantly, the findings in this thesis could lead to discoveries that expand our knowledge of epileptogenesis, opening the door for the development of novel therapies.