Plasmin-resistant PSD-95 inhibitors resolve effect-modifying drug-drug interactions between alteplase and nerinetide in acute stroke
| Autor: | J. David Garman, Michael Tymianski, Zhanxin Ji, Xiujun Sun, Diana Mayor-Nunez, Lucy Teves |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Drug Plasmin medicine.medical_treatment media_common.quotation_subject Pharmacology Neuroprotection Brain Ischemia Brain ischemia 03 medical and health sciences 0302 clinical medicine Pharmacokinetics medicine Thrombolytic Agent Animals Drug Interactions Fibrinolysin Acute stroke media_common Protease business.industry General Medicine medicine.disease Antifibrinolytic Agents Rats Stroke 030104 developmental biology Tissue Plasminogen Activator business Disks Large Homolog 4 Protein 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Science translational medicine. 13(588) |
| ISSN: | 1946-6242 |
| Popis: | Neuroprotection for acute ischemic stroke is achievable with the eicosapeptide nerinetide, an inhibitor of the protein-protein interactions of the synaptic scaffolding protein PSD-95. However, nerinetide is subject to proteolytic cleavage if administered after alteplase, a standard-of-care thrombolytic agent that nullifies nerinetide's beneficial effects. Here, we showed, on the basis of pharmacokinetic data consistent between rats, primates, and humans, that in a rat model of embolic middle cerebral artery occlusion (eMCAO), nerinetide maintained its effectiveness when administered before alteplase. Because of its short plasma half-life, it can be followed by alteplase within minutes without reducing its neuroprotective effectiveness. In addition, the problem of protease sensitivity is solved by substituting cleavage-prone amino acids from their l- to their d-enantiomeric form. Treatment of rats subjected to eMCAO with such an agent, termed d-Tat-l-2B9c, eliminated protease sensitivity and maintained neuroprotective effectiveness. Our data suggest that both the clinical-stage PSD-95 inhibitor nerinetide and protease-resistant agents such as d-Tat-l-2B9c may be practically integrated into existing stroke care workflows and standards of care. |
| Databáze: | OpenAIRE |
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