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The blood-brain barrier (BBB) is a formidable physical and enzymatic barrier that tightly controls the passage of molecules from the blood to the brain. In fact, less than 2 % of all potential neurotherapeutics are able to cross it. Here, by applying the retro-enantio approach to a peptide that targets the transferrin receptor, a full protease-resistant peptide with the capacity to act as a BBB shuttle was obtained and thus enabled the transport of a variety of cargos into the central nervous system.

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Here we studied the capacity of N-MePhe-(N-MePhe)(3)-CONH(2), Cha-(N-MePhe)(3)-CONH(2), and 2Nal-(N-MePhe)(3)-CONH(2) to carry various drugs (cargos) in in vitro blood-brain barrier (BBB) models in order to determine the versatility of these peptides as BBB-shuttles for drug delivery to the brain. Using SPPS, the peptides were coupled to GABA, Nip, and ALA to examine their passive BBB permeation by means of PAMPA and their lipophilicity by IAMC. Unaided, these nonpermeating drugs alone did not cross the PAMPA barrier and the BBB passively; however, the peptides tested as potential BBB shuttles transferred them by passive transfer through the PAMPA phospholipid. The permeability of peptides that showed the highest permeability in PAMPA, and Ac-N-MePhe-(N-MePhe)(3)-CONH(2) as the parent peptide was also examined in bovine brain microvessel endothelial cells (BBMECs). These peptide-based BBB shuttles open up the possibility to overcome the formidable obstacle of the BBB, thereby achieving drug delivery to the brain.

Matrix metalloproteinases (MMPs) are synthesized by neurons and glia and released into the extracellular space, where they act as modulators of neuroplasticity and neuroinflammatory agents. Development of epilepsy (epileptogenesis) is associated with increased expression of MMPs and therefore they may represent potential therapeutic drug targets. Using qPCR and immunohistochemistry, we studied the expression of MMPs and their endogenous inhibitors TIMPs, in patients with status epilepticus (SE) or temporal lobe epilepsy (TLE), and in a rat TLE model. Furthermore, we tested the MMP2/9 inhibitor IPR-179 in the rapid kindling rat model and in the intrahippocampal kainic-acid mouse model. In both human and experimental epilepsy, MMP and TIMP expression was persistently dysregulated in the hippocampus compared to controls. IPR-179 treatment reduced seizure severity in the rapid kindling model and reduced the number of spontaneous seizures in the kainic-acid model (during and up to 7 weeks after delivery) without side effects while improving cognitive behavior. Moreover, our data suggest that IPR-179 prevented an MMP2/9-dependent switch-off normally restraining network excitability during the activity period. Since increased MMP expression is a prominent hallmark of the human epileptogenic brain and the MMP inhibitor IPR-179 has antiseizure and antiepileptogenic effects in rodent epilepsy models and attenuates seizure-induced cognitive decline, it deserves further investigation in clinical trials. Funding: The research leading to these results has received funding from the European Union's