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Early treatment with minocycline following stroke in rats improves functional recovery and differentially modifies responses of peri-infarct microglia and astrocytes.
J Neuroinflammation 2019; 16(1):6JN

Abstract

BACKGROUND

Altered neuronal connectivity in peri-infarct tissue is an important contributor to both the spontaneous recovery of neurological function that commonly develops after stroke and improvements in recovery that have been induced by experimental treatments in animal models. Microglia and astrocytes are primary determinants of the environment in peri-infarct tissue and hence strongly influence the potential for neuronal plasticity. However, the specific roles of these cells and the timing of critical changes in their function are not well understood. Minocycline can protect against ischemic damage and promote recovery. These effects are usually attributed, at least partially, to the ability of this drug to suppress microglial activation. This study tested the ability of minocycline treatment early after stroke to modify reactive responses in microglia and astrocytes and improve recovery.

METHODS

Stroke was induced by photothrombosis in the forelimb sensorimotor cortex of Sprague-Dawley rats. Minocycline was administered for 2 days after stroke induction and the effects on forelimb function assessed up to 28 days. The responses of peri-infarct Iba1-positive cells and astrocytes were evaluated using immunohistochemistry and Western blots.

RESULTS

Initial characterization showed that the numbers of Iba1-positive microglia and macrophages decreased in peri-infarct tissue at 24 h then increased markedly over the next few days. Morphological changes characteristic of activation were readily apparent by 3 h and increased by 24 h. Minocycline treatment improved the rate of recovery of motor function as measured by a forelimb placing test but did not alter infarct volume. At 3 days, there were only minor effects on core features of peri-infarct microglial reactivity including the morphological changes and increased density of Iba1-positive cells. The treatment caused a decrease of 57% in the small subpopulation of cells that expressed CD68, a marker of phagocytosis. At 7 days, the expression of glial fibrillary acidic protein and vimentin was markedly increased by minocycline treatment, indicating enhanced reactive astrogliosis.

CONCLUSIONS

Early post-stroke treatment with minocycline improved recovery but had little effect on key features of microglial activation. Both the decrease in CD68-positive cells and the increased activation of astrogliosis could influence neuronal plasticity and contribute to the improved recovery.

Authors+Show Affiliations

Centre for Neuroscience, College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.Centre for Neuroscience, College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.Centre for Neuroscience, College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.Hunter Medical Research Institute; School of Biomedical Medical Sciences and Pharmacy, University of Newcastle Priority Research Centre in Stroke and Traumatic Brain Injury, Newcastle, NSW, Australia.Hunter Medical Research Institute; School of Biomedical Medical Sciences and Pharmacy, University of Newcastle Priority Research Centre in Stroke and Traumatic Brain Injury, Newcastle, NSW, Australia.Centre for Neuroscience, College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.Centre for Neuroscience, College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.Centre for Neuroscience, College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia. neil.sims@flinders.edu.au.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30626393

Citation

Yew, Wai Ping, et al. "Early Treatment With Minocycline Following Stroke in Rats Improves Functional Recovery and Differentially Modifies Responses of Peri-infarct Microglia and Astrocytes." Journal of Neuroinflammation, vol. 16, no. 1, 2019, p. 6.
Yew WP, Djukic ND, Jayaseelan JSP, et al. Early treatment with minocycline following stroke in rats improves functional recovery and differentially modifies responses of peri-infarct microglia and astrocytes. J Neuroinflammation. 2019;16(1):6.
Yew, W. P., Djukic, N. D., Jayaseelan, J. S. P., Walker, F. R., Roos, K. A. A., Chataway, T. K., ... Sims, N. R. (2019). Early treatment with minocycline following stroke in rats improves functional recovery and differentially modifies responses of peri-infarct microglia and astrocytes. Journal of Neuroinflammation, 16(1), p. 6. doi:10.1186/s12974-018-1379-y.
Yew WP, et al. Early Treatment With Minocycline Following Stroke in Rats Improves Functional Recovery and Differentially Modifies Responses of Peri-infarct Microglia and Astrocytes. J Neuroinflammation. 2019 Jan 9;16(1):6. PubMed PMID: 30626393.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Early treatment with minocycline following stroke in rats improves functional recovery and differentially modifies responses of peri-infarct microglia and astrocytes. AU - Yew,Wai Ping, AU - Djukic,Natalia D, AU - Jayaseelan,Jaya S P, AU - Walker,Frederick R, AU - Roos,Karl A A, AU - Chataway,Timothy K, AU - Muyderman,Hakan, AU - Sims,Neil R, Y1 - 2019/01/09/ PY - 2018/10/10/received PY - 2018/11/26/accepted PY - 2019/1/11/entrez PY - 2019/1/11/pubmed PY - 2019/4/16/medline KW - Astrocytes KW - Focal ischemia KW - Functional recovery KW - Microglia KW - Minocycline KW - Peri-infarct KW - Photothrombosis KW - Stroke SP - 6 EP - 6 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 16 IS - 1 N2 - BACKGROUND: Altered neuronal connectivity in peri-infarct tissue is an important contributor to both the spontaneous recovery of neurological function that commonly develops after stroke and improvements in recovery that have been induced by experimental treatments in animal models. Microglia and astrocytes are primary determinants of the environment in peri-infarct tissue and hence strongly influence the potential for neuronal plasticity. However, the specific roles of these cells and the timing of critical changes in their function are not well understood. Minocycline can protect against ischemic damage and promote recovery. These effects are usually attributed, at least partially, to the ability of this drug to suppress microglial activation. This study tested the ability of minocycline treatment early after stroke to modify reactive responses in microglia and astrocytes and improve recovery. METHODS: Stroke was induced by photothrombosis in the forelimb sensorimotor cortex of Sprague-Dawley rats. Minocycline was administered for 2 days after stroke induction and the effects on forelimb function assessed up to 28 days. The responses of peri-infarct Iba1-positive cells and astrocytes were evaluated using immunohistochemistry and Western blots. RESULTS: Initial characterization showed that the numbers of Iba1-positive microglia and macrophages decreased in peri-infarct tissue at 24 h then increased markedly over the next few days. Morphological changes characteristic of activation were readily apparent by 3 h and increased by 24 h. Minocycline treatment improved the rate of recovery of motor function as measured by a forelimb placing test but did not alter infarct volume. At 3 days, there were only minor effects on core features of peri-infarct microglial reactivity including the morphological changes and increased density of Iba1-positive cells. The treatment caused a decrease of 57% in the small subpopulation of cells that expressed CD68, a marker of phagocytosis. At 7 days, the expression of glial fibrillary acidic protein and vimentin was markedly increased by minocycline treatment, indicating enhanced reactive astrogliosis. CONCLUSIONS: Early post-stroke treatment with minocycline improved recovery but had little effect on key features of microglial activation. Both the decrease in CD68-positive cells and the increased activation of astrogliosis could influence neuronal plasticity and contribute to the improved recovery. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/30626393/Early_treatment_with_minocycline_following_stroke_in_rats_improves_functional_recovery_and_differentially_modifies_responses_of_peri_infarct_microglia_and_astrocytes_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-018-1379-y DB - PRIME DP - Unbound Medicine ER -