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Methylprednisolone Reduces Persistent Post-ischemic Inflammation in a Rat Hypoxia-Ischemia Model of Perinatal Stroke

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Abstract

In perinatal stroke, the initial injury results in a chronic inflammatory response caused by the release of proinflammatory cytokines, gliosis and microglia activation. This chronic and ongoing inflammatory response exacerbates the brain injury, often resulting in encephalopathy and cerebral palsy (CP). Using a neonatal rat model of hypoxia-ischemia (HI) at postnatal day (P)7, we demonstrated that chronic inflammation is persistent and continues into the tertiary phase of perinatal stroke and can be attenuated by the administration of methylprednisolone sodium-succinate (MPSS, 30 mg/kg), a US Food and Drug Administration (FDA) approved anti-inflammatory agent. The inflammatory response was assessed by real-time quantitative PCR and ELISA for markers of inflammation (CCL3, CCL5, IL18 and TNFα). Structural changes were evaluated by histology (LFB/H&E), while cellular changes were assessed by Iba-1, ED1, GFAP, NeuN, Olig2 and CC1 immunostaining. Functional deficits were assessed with the Cylinder test and Ladder Rung Walking test. MPSS was injected 14 days after HI insult to attenuate chronic inflammation. In neonatal conditions such as CP, P21 is a clinically relevant time-point in rodents, corresponding developmentally to a 2-year-old human. Administration of MPSS resulted in reduced structural damage (corpus callosum, cortex, hippocampus, striatum), gliosis and reactive microglia and partial restoration of the oligodendrocyte population. Furthermore, significant behavioural recovery was observed. In conclusion, we demonstrated that administration of MPSS during the tertiary phase of perinatal stroke results in attenuation of the chronic inflammatory response, leading to pathophysiological and functional recovery. This work validates the high clinical impact of MPSS to treat neonatal conditions linked to chronic inflammation.

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Funding

This study was funded by the Kids Brain Health Network and Ontario Brain Institute.

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Author notes

  1. Svetlana Altamentova and Prakasham Rumajogee contributed equally to this work.

Authors and Affiliations

  1. Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada

    Svetlana Altamentova, Prakasham Rumajogee, James Hong, Stephanie R. Beldick, Sei Joon Park, Albert Yee & Michael G. Fehlings

  2. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    James Hong, Stephanie R. Beldick & Michael G. Fehlings

  3. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada

    Michael G. Fehlings

  4. Division of Neurosurgery, Toronto Western Hospital, University Health Network, 399 Bathurst St. Suite 4WW-449, Toronto, Ontario, M5T 2S8, Canada

    Michael G. Fehlings

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  1. Svetlana Altamentova
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Correspondence to Michael G. Fehlings.

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Experimental procedures, animal use and care were approved by the Animal Care Committee at the University Health Network in accordance with the policies and procedures outlined by the Canadian Council of Animal Care.

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Altamentova, S., Rumajogee, P., Hong, J. et al. Methylprednisolone Reduces Persistent Post-ischemic Inflammation in a Rat Hypoxia-Ischemia Model of Perinatal Stroke. Transl. Stroke Res. 11, 1117–1136 (2020). https://doi.org/10.1007/s12975-020-00792-2

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