• Hiroki Uchikawa, Koki Kameno, Keitaro Kai, Sosho Kajiwara, Kana Fujimori, Ken Uekawa, Yukio Fujiwara, Akitake Mukasa, Shokei Kim-Mitsuyama, and Yu Hasegawa.
• Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
• Neurocrit Care. 2023 Aug 1; 39 (1): 207217207-217.

BackgroundBrain perivascular macrophages (PVMs) are potential treatment targets for subarachnoid hemorrhage (SAH), and previous studies revealed that their depletion by clodronate (CLD) improved outcomes after experimental SAH. However, the underlying mechanisms are not well understood. Therefore, we investigated whether reducing PVMs by CLD pretreatment improves SAH prognosis by inhibiting posthemorrhagic impairment of cerebral blood flow (CBF).MethodsIn total, 80 male Sprague-Dawley rats received an intracerebroventricular injection of the vehicle (liposomes) or CLD. Subsequently, the rats were categorized into the prechiasmatic saline injection (sham) and blood injection (SAH) groups after 72 h. We assessed its effects on weak and severe SAH, which were induced by 200- and 300-µL arterial blood injections, respectively. In addition, neurological function at 72 h and CBF changes from before the intervention to 5 min after were assessed in rats after sham/SAH induction as the primary and secondary end points, respectively.ResultsCLD significantly reduced PVMs before SAH induction. Although pretreatment with CLD in the weak SAH group provided no additive effects on the primary end point, rats in the severe SAH group showed significant improvement in the rotarod test. In the severe SAH group, CLD inhibited acute reduction of CBF and tended to decrease hypoxia-inducible factor 1α expression. Furthermore, CLD reduced the number of PVMs in rats subjected to sham and SAH surgery, although no effects were observed in oxidative stress and inflammation.ConclusionsOur study proposes that pretreatment with CLD-targeting PVMs can improve the prognosis of severe SAH through a candidate mechanism of inhibition of posthemorrhagic CBF reduction.© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.

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