Examination of central nervous system by functional observation battery after massive intravenous infusion of carbon monoxide-bound and oxygen-bound hemoglobin vesicles in rats

Hiromi Sakai; Shunichi Yasuda; Chie Okuda; Tetsuya Yamada; Keita Owaki; Yoji Miwa

doi:10.1016/j.crphar.2022.100135

Examination of central nervous system by functional observation battery after massive intravenous infusion of carbon monoxide-bound and oxygen-bound hemoglobin vesicles in rats

Curr Res Pharmacol Drug Discov. 2022 Oct 4:3:100135. doi: 10.1016/j.crphar.2022.100135. eCollection 2022.

Authors

Hiromi Sakai¹, Shunichi Yasuda², Chie Okuda^{1

3}, Tetsuya Yamada², Keita Owaki², Yoji Miwa²

Affiliations

¹ Department of Chemistry, Nara Medical University, Kashihara, Nara, Japan.
² Hashima Laboratory, Nihon Bioresearch Inc, Hashima, Gifu, Japan.
³ Department of Anesthesiology, Nara Medical University, Kashihara, Nara, Japan.

Abstract

Carbon monoxide (CO) is known as a toxic gas inducing "CO poisoning", which acutely affects the central nervous system (CNS) and which persistently affects brain functions depending on the exposure time and CO concentration. By contrast, in pathological rodent models, intravenous infusion of CO-bound hemoglobin vesicles (CO-HbV) has shown various beneficial effects such as anti-oxidative and anti-inflammatory reactions. This study assessed effects of CO-HbV infusion on CNS using a functional observation battery, sensory reflexes, grip strength, and landing foot splay measurements. The test fluids were CO-HbV and O₂-bound HbV (O₂-HbV) suspended in saline ([Hb] = 10 g/dL), and saline alone for comparison. The rats received either 16 or 32 mL/kg of fluid intravenously at 1.5 mL/min/kg. Observations were made before infusion, and at 5 min, 4, 8, 24, 48 and 72 h after infusion. Massive doses of 16 and 32 mL/kg respectively corresponded to about 29 and 57% of the whole circulating blood volume (56 mL/kg). No toxicological effect was observed in any measurement item for any group in comparison to the control saline infusion group. Histopathological examination of hippocampal tissue at 14 days after infusion showed the number of necrotic cells to be minimal. Results obtained from rats in this experiment suggest that the massive intravenous infusion of CO-HbV yields beneficial anti-oxidative and anti-inflammatory effects without showing CO-poisoning-related symptoms of CNS damage.

Keywords: Artificial oxygen carriers; Artificial red cells; Blood substitutes; Carbon monoxide poisoning; Liposome; Transfusion alternative.