There is increasing interest in nose-to-brain delivery as an innovative drug delivery strategy for neurodegenerative disorders such as Parkinson’s or Alzheimer’s disease. The unique anatomy of the nose-brain interface facilitates direct drug transport via the olfactory and trigeminal pathways to the brain, bypassing the blood–brain barrier. Different administration techniques as well as advanced drug formulations like targeted nanoparticles and thermoresponsive systems have been explored to improve the delivery efficiency and the therapeutic efficacy. This review provides an up-to-date perspective on this fast-developing field, and discusses different studies on safety and pharmacokinetic properties. A thorough evaluation of preclinical and clinical studies reveals both promises and challenges of this delivery method, highlighting approved drugs for the treatment of epilepsy and migraine that successfully utilize intranasal routes. The current landscape of research on nose-to-brain delivery is critically discussed, and a rationale is provided for ongoing research to optimize therapeutic strategies.

In the European Union (EU) millions of laboratory mice are used and killed for experimental and other scientific purposes each year. Although controversially discussed, the use of carbon dioxide (CO₂) is still permitted for killing rodents according to the Directive 2010/63/EU. Within the scope of refinement, our aim was to investigate if isoflurane and sevoflurane are an appropriate alternative killing method to CO₂ in mice. Different concentrations of CO₂ (filling rates of 20%, 60%, 100%; CO₂ 20, 60, 100), isoflurane (Iso 2%, 5%) and sevoflurane (Sevo 4.8%, 8%) were compared in two mouse strains (NMRI, C57Bl/6J) using a broad spectrum of behavioral parameters, including the approach-avoidance test, and analyzing blood for stress parameters (glucose, adrenaline, noradrenaline). We focused in our study on the period from the beginning of the gas inlet to loss of consciousness, as during this period animals are able to perceive pain and distress. Our results show that only higher concentrations of CO₂ (CO₂ 60, 100) and isoflurane (5%) induced surgical tolerance within 300 s in both strains, with CO₂ 100 being the fastest acting inhalant anesthetic. The potency of halogenated ethers depended on the mouse strain, with C57Bl/6J being more susceptible than NMRI mice. Behavioral analysis revealed no specific signs of distress, e. g. stress-induced grooming, and pain, i. e. audible vocalizations, for all inhalant gases. However, adrenaline and noradrenaline plasma concentrations were increased, especially in NMRI mice exposed to CO₂ in high concentrations, whereas we did not observe such increase in animals exposed to isoflurane or sevoflurane. Escape latencies in the approach-avoidance test using C57Bl/6J mice did not differ between the three inhalant gases, however, some animals became recumbent during isoflurane and sevoflurane but not during CO₂ exposure. The rise in catecholamine concentrations suggests that CO₂ exposure might be linked to a higher stress response compared to isoflurane and sevoflurane exposure, although we did not observe a behavioral correlate for that. Follow-up studies investigating other fast-acting stress hormones and central anxiety circuits are needed to confirm our findings.

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.