Immunomodulation With Local, Sustained Delivery of Pituitary Adenylate Cyclase Activating Polypeptide Results in Improved Functional Recovery in Stroke-Injured Mice

Ho, Eric; Li, David Xinzheyang; Cui, Hong; Akbar, Dania; Siu, Ricky; Morshead, Cindi M; Chatenet, David ORCID: https://orcid.org/0000-0002-7270-4328 et Shoichet, Molly S (2025). Immunomodulation With Local, Sustained Delivery of Pituitary Adenylate Cyclase Activating Polypeptide Results in Improved Functional Recovery in Stroke-Injured Mice Advanced Healthcare Materials , nº 2500765. pp. 1-15. DOI: 0.1002/adhm.202500765.

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Résumé

Following ischemic stroke, astrocytes and microglia become activated and create a hostile microenvironment that can exacerbate brain damage, yet these cells also contribute to tissue regeneration. Pituitary adenylate cyclase activating polypeptide (PACAP) is a promising neuroprotective peptide that modulates microglia toward a pro-reparative phenotype, however, its short half-life in vivo and dose-limited off-target effects have made systemic delivery untenable. Local delivery presents a promising alternative. To this end, we developed a hydrogel-nanoparticle composite for the minimally invasive, local delivery of PACAP to the brain and tested this strategy in chemically-induced, endothelin-1 stroke-injured mice. We demonstrate that prolonged delivery of PACAP improved the physical strength and mobility of mice for up to 28 days after stroke. The treatment decreased the number of apoptotic neurons in the stroke microenvironment, increased neuron survival at 28 days post-stroke, and attenuated reactive astrogliosis and microglia activation. PACAP stimulation resulted in increased Iba1+Arg1+ pro-reparative microglia and decreased Iba1+CD86+ pro-inflammatory microglia. Furthermore, PACAP stimulation significantly decreased pro-inflammatory GFAP+LCN2+ and GFAP+S100 beta+ astrocytes versus controls. This phenotypic shift in microglia and astrocytes may account for the functional improvements post stroke and paves the way for local delivery of new therapeutic strategies targeting the immune response for stroke treatment.

Type de document:	Article
Informations complémentaires:	The authors are grateful for funding from the Canadian Institutes for Health Research (CIHR) and the Natural Science and Engineering Re- search Council (NSERC) for funding through the Collaborative Health Re- search Program (CHRP to CMM and MSS). The authors are grateful for additional support: NSERC PGSD to EH, NSERC Vanier CGS to DXL, Dis- covery and Herzberg Gold Medal to MSS.
Mots-clés libres:	PACAP; astrocytes; electrostatic controlled release; hydrogel; inflammation; microglia; nanoparticle; pituitary adenylate cyclase activating polypeptide; stroke
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	28 août 2025 18:47
Dernière modification:	28 août 2025 18:47
URI:	https://espace.inrs.ca/id/eprint/16580

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