MRI Heralds Secondary Nigral Lesion After Brain Ischemia in Mice: a Secondary Time Window for Neuroprotection

Overview

Journal J Cereb Blood Flow Metab

Publisher Sage Publications

Specialties Cardiology & Vascular Diseases
Endocrinology
Neurology

Date 2015 Jul 2

PMID 26126863

Citations 11

Authors

Vincent Prinz

Anna-Maria Hetzer

Susanne Muller

Mustafa Balkaya

Christoph Leithner

Golo Kronenberg

Matthias Endres

Affiliations

Soon will be listed here.

Abstract

Cerebral ischemia in the territory of the middle cerebral artery (MCA) can induce delayed neuronal cell death in the ipsilateral substantia nigra (SN) remote from the primary ischemic lesion. This exofocal postischemic neuronal degeneration (EPND) may worsen stroke outcomes. However, the mechanisms leading to EPND are poorly understood. Here, we studied the time course of EPND via sequential magnetic resonance imaging (MRI) and immunohistochemistry for up to 28 days after 30 minutes' occlusion of the MCA (MCAo) and reperfusion in the mouse. Furthermore, the effects of delayed treatment with FK506 and MK-801 on the development of EPND were investigated. Secondary neuronal degeneration in the SN occurred within the first week after MCAo and was characterized by a marked neuronal cell loss on histology. Sequential neuroimaging examinations revealed transient MRI changes, which were detectable as early as day 4 after MCAo and thus heralding histologic evidence of EPND. Treatment with MK-801, an established anti-excitotoxic agent, conferred protection against EPND even when initiated days after the initial ischemic event, which was not evident with FK506. Our findings define a secondary time window for delayed neuroprotection after stroke, which may provide a promising target for the development of novel therapies.

Citing Articles

Out of the core: the impact of focal ischemia in regions beyond the penumbra.

Koukalova L, Chmelova M, Amlerova Z, Vargova L Front Cell Neurosci. 2024; 18:1336886.

PMID: 38504666 PMC: 10948541. DOI: 10.3389/fncel.2024.1336886.

Enhancing Post-Stroke Rehabilitation and Preventing Exo-Focal Dopaminergic Degeneration in Rats-A Role for Substance P.

Frase S, Loffler F, Hosp J Int J Mol Sci. 2022; 23(7).

PMID: 35409207 PMC: 8999050. DOI: 10.3390/ijms23073848.

Altered circular RNA expression profiles in the non-ischemic thalamus in focal cortical infarction mice.

Li F, Li C, Li X, Li Y, Zhong Y, Ling L Aging (Albany NY). 2020; 12(13):13206-13219.

PMID: 32639948 PMC: 7377861. DOI: 10.18632/aging.103424.

Neuroprotective Effects of Salidroside on Cerebral Ischemia/Reperfusion-Induced Behavioral Impairment Involves the Dopaminergic System.

Zhong Z, Han J, Zhang J, Xiao Q, Chen J, Zhang K Front Pharmacol. 2020; 10:1433.

PMID: 31920641 PMC: 6923222. DOI: 10.3389/fphar.2019.01433.

Bone Marrow Stromal Cells Alleviate Secondary Damage in the Substantia Nigra After Focal Cerebral Infarction in Rats.

Jin J, Tang Y, Li K, Zuo X, Zhan L, Sun W Front Cell Neurosci. 2019; 13:338.

PMID: 31396057 PMC: 6668054. DOI: 10.3389/fncel.2019.00338.

References

Zhao F, Kuroiwa T, Miyasaka N, Nagaoka T, Nakane M, Tamura A . Characteristic changes in T(2)-value, apparent diffusion coefficient, and ultrastructure of substantia nigra evolving exofocal postischemic neuronal death in rats. Brain Res. 2001; 895(1-2):238-44. DOI: 10.1016/s0006-8993(00)03281-9. View

Zhao F, Kuroiwa T, Miyasaka N, Nagaoka T, Nakane M, Tamura A . Ultrastructural and MRI study of the substantia nigra evolving exofocal post-ischemic neuronal death in the rat. Neuropathology. 2002; 22(3):91-105. DOI: 10.1046/j.1440-1789.2002.00437.x. View

Nakane M, Teraoka A, Asato R, Tamura A . Degeneration of the ipsilateral substantia nigra following cerebral infarction in the striatum. Stroke. 1992; 23(3):328-32. DOI: 10.1161/01.str.23.3.328. View

Yamada K, Goto S, Yoshikawa M, Ushio Y . Gabaergic transmission and tyrosine hydroxylase expression in the nigral dopaminergic neurons: an in vivo study using a reversible ischemia model of rats. Neuroscience. 1996; 73(3):783-9. DOI: 10.1016/0306-4522(96)00041-3. View

Ogawa T, Okudera T, Inugami A, Noguchi K, Kado H, Yoshida Y . Degeneration of the ipsilateral substantia nigra after striatal infarction: evaluation with MR imaging. Radiology. 1997; 204(3):847-51. DOI: 10.1148/radiology.204.3.9280270. View

Soriano M, Justicia C, Ferrer I, Rodriguez-Farre E, Planas A . Striatal infarction in the rat causes a transient reduction of tyrosine hydroxylase immunoreactivity in the ipsilateral substantia nigra. Neurobiol Dis. 1997; 4(5):376-85. DOI: 10.1006/nbdi.1997.0166. View

Dirnagl U, Iadecola C, Moskowitz M . Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999; 22(9):391-7. DOI: 10.1016/s0166-2236(99)01401-0. View

Winter B, Juckel G, Viktorov I, Katchanov J, Gietz A, Sohr R . Anxious and hyperactive phenotype following brief ischemic episodes in mice. Biol Psychiatry. 2005; 57(10):1166-75. DOI: 10.1016/j.biopsych.2005.02.010. View

Macleod M, OCollins T, Horky L, Howells D, Donnan G . Systematic review and metaanalysis of the efficacy of FK506 in experimental stroke. J Cereb Blood Flow Metab. 2005; 25(6):713-21. DOI: 10.1038/sj.jcbfm.9600064. View

10.

Kinoshita T, Moritani T, Shrier D, Wang H, Hiwatashi A, Numaguchi Y . Secondary degeneration of the substantia nigra and corticospinal tract after hemorrhagic middle cerebral artery infarction: diffusion-weighted MR findings. Magn Reson Med Sci. 2005; 1(3):175-8. DOI: 10.2463/mrms.1.175. View

11.

Nestler E, Carlezon Jr W . The mesolimbic dopamine reward circuit in depression. Biol Psychiatry. 2006; 59(12):1151-9. DOI: 10.1016/j.biopsych.2005.09.018. View

12.

Prinz V, Laufs U, Gertz K, Kronenberg G, Balkaya M, Leithner C . Intravenous rosuvastatin for acute stroke treatment: an animal study. Stroke. 2007; 39(2):433-8. DOI: 10.1161/STROKEAHA.107.492470. View

13.

Becker C, Jick S, Meier C . Risk of stroke in patients with idiopathic Parkinson disease. Parkinsonism Relat Disord. 2009; 16(1):31-5. DOI: 10.1016/j.parkreldis.2009.06.005. View

14.

Moskowitz M, Lo E, Iadecola C . The science of stroke: mechanisms in search of treatments. Neuron. 2010; 67(2):181-98. PMC: 2957363. DOI: 10.1016/j.neuron.2010.07.002. View

15.

Prinz V, Endres M . Statins and stroke: prevention and beyond. Curr Opin Neurol. 2010; 24(1):75-80. DOI: 10.1097/WCO.0b013e3283424c53. View

16.

Engel O, Kolodziej S, Dirnagl U, Prinz V . Modeling stroke in mice - middle cerebral artery occlusion with the filament model. J Vis Exp. 2011; (47). PMC: 3182649. DOI: 10.3791/2423. View

17.

Mukherjee D, Patil C . Epidemiology and the global burden of stroke. World Neurosurg. 2011; 76(6 Suppl):S85-90. DOI: 10.1016/j.wneu.2011.07.023. View

18.

Zhang J, Zhang Y, Xing S, Liang Z, Zeng J . Secondary neurodegeneration in remote regions after focal cerebral infarction: a new target for stroke management?. Stroke. 2012; 43(6):1700-5. DOI: 10.1161/STROKEAHA.111.632448. View

19.

Kronenberg G, Balkaya M, Prinz V, Gertz K, Ji S, Kirste I . Exofocal dopaminergic degeneration as antidepressant target in mouse model of poststroke depression. Biol Psychiatry. 2012; 72(4):273-81. DOI: 10.1016/j.biopsych.2012.02.026. View

20.

Rodriguez-Grande B, Blackabey V, Gittens B, Pinteaux E, Denes A . Loss of substance P and inflammation precede delayed neurodegeneration in the substantia nigra after cerebral ischemia. Brain Behav Immun. 2012; 29:51-61. DOI: 10.1016/j.bbi.2012.11.017. View