Initial development of an implantable drug delivery device for the treatment of epilepsy
AffiliationMelbourne Veterinary School
Document TypePhD thesis
Access StatusOpen Access
© 2018 Dr Sébastien Hyacinthe Bauquier
Epilepsy is a chronic neurological condition, characterized by recurrent seizures. Treatment with conventional anti-epileptic drugs (AED) results in only 33% of patients having no seizure recurrence after a prolonged period. Some evidence suggests that the lack of effectiveness of AED penetration into the brain parenchyma could be one of the mechanisms for resistance to treatment. Furthermore, AED side effects often prevent large increases in their dose. It was for these reasons that a new alternative approach to therapy, intracranial implantation of polymer-based drug delivery systems aimed at improving the bioavailability of AED, was investigated in this PhD research project. Genetic Absent Epilepsy Rats from Strasbourg (GAERS) is a strain of rat that has 100% of the animals with recurrent generalised non-convulsive seizures. This animal model has become the gold standard to study the mechanisms underlying absence epilepsy. After validating an automated spike and wave discharges (SWDs) detection algorithm applied to GAERS’ electroencephalograms (EEG) and demonstrating some effects of enrofloxacin on the GAERS’ epileptic activity, in vitro characterisation and in vivo testing of the antiepileptic efficacy of Poly(D,L-lactide-co-glycolide) (PLGA) polymers loaded with anticonvulsants, either phenytoin or lacosamide, were performed. PLGA is a biodegradable copolymer that it is very well tolerated by the brain and can be used as a passive release substrate. In prospective randomized masked experiments, GAERS underwent surgery for implantation of skull electrodes, skull electrodes and blank polymers, or skull electrodes and AED loaded polymers. The polymers were implanted bilaterally and subdurally on the surface of the cortex. Electroencephalogram recordings were started at day 7 post-surgery and continued for eight weeks. The number of SWDs and mean duration of one SWD were compared week-by-week between the groups. Although temporary changes were seen, phenytoin loaded PLGA polymer sheets did not decrease seizure activity in GAERS. However lacosamide loaded PLGA polymer sheets affected seizure activity in GAERS by decreasing the mean duration of SWDs for a sustained period of up to 7 weeks. This provided proof of concept that intracranial implantation of polymer-based drug delivery systems could be used in the treatment of epilepsy. The last chapter of this thesis evaluated the in vivo biocompatibility of Polypyrrole (PPy) implanted subdurally and unilaterally on the surface of the motor cortex in GAERS. Polypyrrole offers the advantage of being electrically conductive which could allow a controlled release of the anti-epileptic medications. Due to the absence of evidence of toxic injury or immune mediated inflammation, it was concluded that PPy offers good histocompatibility with central nervous system cells. Furthermore, the comparison of immunohistochemical scores reveals that the amount of neuronal death and gliosis was significantly less in the PPy side than in the sham surgery side of the cortices (p values of 0.005 and 0.002 respectively) implying that the application of PPy could protect the CNS tissue after surgery. With improvements in polymer technologies and episodic release offering potentially much longer lasting release durations, intracranial polymer-based drug delivery systems may provide an effective therapeutic strategy for chronic epilepsy. While the development of such an antiepileptic device is worthwhile but still years away, the development of an implantable device combining the potential neuroprotective effect of PPy and an anti-inflammatory drug like dexamethasone would certainly be quicker to develop.
Keywordsepilepsy; seizure detection; polymer; poly(D,L-lactide); polypyrrole; lacosamide; phenytoin; GAERS; enrofloxacin
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