Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

Abstract

Epilepsies are common chronic neurological diseases characterized by recurrent unprovoked seizures of central origin. The mainstay of treatment involves symptomatic suppression of seizures with systemically applied antiseizure drugs (ASDs). Systemic pharmacotherapies for epilepsies are facing two main challenges. First, adverse effects from (often life-long) systemic drug treatment are common, and second, about one-third of patients with epilepsy have seizures refractory to systemic pharmacotherapy. Especially the drug resistance in epilepsies remains an unmet clinical need despite the recent introduction of new ASDs. Apart from other hypotheses, epilepsy-induced alterations of the blood–brain barrier (BBB) are thought to prevent ASDs from entering the brain parenchyma in necessary amounts, thereby being involved in causing drug-resistant epilepsy. Although an invasive procedure, bypassing the BBB by targeted intracranial drug delivery is an attractive approach to circumvent BBB-associated drug resistance mechanisms and to lower the risk of systemic and neurologic adverse effects. Additionally, it offers the possibility of reaching higher local drug concentrations in appropriate target regions while minimizing them in other brain or peripheral areas, as well as using otherwise toxic drugs not suitable for systemic administration. In our review, we give an overview of experimental and clinical studies conducted on direct intracranial drug delivery in epilepsies. We also discuss challenges associated with intracranial pharmacotherapy for epilepsies.

Current knowledge and challenges associated with targeted delivery of neurotrophic factors into the central nervous system: focus on available approaches

“…The cannula can move in the injection site which can cause incorrect targeting [ 179 ]. Although the parenchyma of CNS restricts the diffusion of proteins [ 185 ], the NTFs can spread through neuronal internalization [ 158 ]. The observations have shown that the NTF-SCs can migrate through the CNS tissue and reach the injury site [ 64 ].…”

“…The observations have shown that the NTF-SCs can migrate through the CNS tissue and reach the injury site [ 64 ]. The direct-injected therapeutics have higher local concentration and longer half-life inside the CNS which can have dual aspects, upregulates their positive effects via presenting the agent directly to the injury site or in some cases can cause neurotoxicity [ 158 , 185 , 186 ]. In intraparenchymal injection, the therapeutic agent can reach deep brain regions like the striatum and hypothalamus that can be more efficient for regeneration [ 179 ].…”

Drug Resistance in Epilepsy: Which Prospect to Tame its Stubbornness?

“…Thus, for targeting either the seizure focus or key propagation pathways, focal treatments of epilepsy upon bypassing the BBB by local drug delivery and neuronal stem cell grafting have been tackled since decades, 69 and were actively pursued. 70 The delivery of ASDs directly to the regions of the brain involved in seizures is meant to include the seizure-stimulated drug release from an implanted pump or an external reservoir, based on the "closed-loop" principle presented above. The fact that focal pharmacological manipulations in the brain, triggered by seizure detection can actually suppress seizure activity was confirmed in animal models, 71 in which ASDs have been successfully delivered to seizure foci in the brain by programmed infusion pumps, acting in response to computer EEG seizure detection.…”

Noise Efficient Integrated Amplifier Designs for Biomedical Applications

“…Novel closed-loop approaches target the treatment of epileptic seizures [10,11]. Algorithms for the interpretation of the EEG [12,13] and the combination with implantable drug-releasing units lead to novel therapeutic strategies for patients [14]. Brain activity mapping of mice with microprobes containing more than a thousand electrodes [15] is now a frequently used method in animal research [15][16][17].…”