The online version of this article (doi:10.1007/s12975-017-0555-1) contains supplementary material, which is available to authorized users.
Vascular contributions to cognitive impairment and dementia (VCID) make up 50% of the cases of dementia. The purpose of this study was to determine the effect of chronic remote ischemic conditioning (C-RIC) on improving long-term (6 months) outcomes and cerebral blood flow (CBF) and collateral formation in a mouse model of VCID. Adult C57BL/6J male mice (10 weeks) were randomly assigned to four different groups: (1) sham-bilateral carotid artery stenosis (BCAS), (2) BCAS + sham RIC, (3) BCAS+C-RIC for 1 month (1MO), and (4) BCAS+C-RIC-4 months (4MO). CBF, cognitive impairment, and functional outcomes were performed up for 6 months after BCAS surgery. The expression of CD31, α-SMA, and myelin basic protein (MBP) was assessed by immunohistochemistry (IHC). Additional set of mice were randomized to sham, BCAS, and BCAS+C-RIC. The cerebrovascular angioarchitecture was studied with micro-CT. RIC therapy for either 1 or 4 months significantly improved CBF, new collateral formation, functional and cognitive outcomes, and prevented white matter damage. There was no difference between C-RIC for 1 or 4 months; IHC studies at 6 months showed an increase in brain CD31 and α-SMA expression indicating increased angiogenesis and MBP indicating preservation of white matter in animals receiving RIC. One month of daily RIC is as effective as 4 months of daily RIC in improving CBF, angiogenesis, and long-term functional outcomes (6 months) in a VCID model. This suggests that 1 month of RIC is sufficient to reduce cognitive impairment and induce beneficial cerebrovascular remodeling.
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Corriveau RA, Bosetti F, Emr M, Gladman JT, Koenig JI, Moy CS, et al. The science of vascular contributions to cognitive impairment and dementia (VCID): a framework for advancing research priorities in the cerebrovascular biology of cognitive decline. Cell Mol Neurobiol. 2016;36(2):281–8. doi: 10.1007/s10571-016-0334-7. CrossRefPubMedPubMedCentral
Verdelho A, Madureira S, Ferro JM, Baezner H, Blahak C, Poggesi A, et al. Physical activity prevents progression for cognitive impairment and vascular dementia: results from the LADIS (Leukoaraiosis and Disability) study. Stroke. 2012;43(12):3331–5. doi: 10.1161/STROKEAHA.112.661793. CrossRefPubMed
Bernbaum M, Menon BK, Fick G, Smith EE, Goyal M, Frayne R, et al. Reduced blood flow in normal white matter predicts development of leukoaraiosis. J Cereb Blood Flow Metab : Off J Int Soc Cereb Blood Flow Metab. 2015; doi: 10.1038/jcbfm.2015.92.
Holland PR, Searcy JL, Salvadores N, Scullion G, Chen G, Lawson G, et al. Gliovascular disruption and cognitive deficits in a mouse model with features of small vessel disease. J Cereb Blood Flow Metab : Off J Int Soc Cereb Blood Flow Metab. 2015;35(6):1005–14. doi: 10.1038/jcbfm.2015.12. CrossRef
Khan MB, Hoda MN, Vaibhav K, Giri S, Wang P, Waller JL, et al. Remote ischemic postconditioning: harnessing endogenous protection in a murine model of vascular cognitive impairment. Transl Stroke Res. 2014; doi: 10.1007/s12975-014-0374-6.
Wakade C, Sukumari-Ramesh S, Laird MD, Dhandapani KM, Vender JR. Delayed reduction in hippocampal postsynaptic density protein-95 expression temporally correlates with cognitive dysfunction following controlled cortical impact in mice. J Neurosurg. 2010;113(6):1195–201. doi: 10.3171/2010.3.JNS091212. CrossRefPubMedPubMedCentral
Luong TN, Carlisle HJ, Southwell A, Patterson PH. Assessment of motor balance and coordination in mice using the balance beam. J Vis Exp. 2011;49 doi: 10.3791/2376.
Klein SM, Vykoukal J, Lechler P, Zeitler K, Gehmert S, Schreml S, et al. Noninvasive in vivo assessment of muscle impairment in the mdx mouse model—a comparison of two common wire hanging methods with two different results. J Neurosci Methods. 2012;203(2):292–7. doi: 10.1016/j.jneumeth.2011.10.001. CrossRefPubMed
Baban B, Hansen AM, Chandler PR, Manlapat A, Bingaman A, Kahler DJ, et al. A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type I IFN signaling following B7 ligation. Int Immunol. 2005;17(7):909–19. doi: 10.1093/intimm/dxh271. CrossRefPubMed
Baban B, Liu JY, Mozaffari MS. Pressure overload regulates expression of cytokines, gammaH2AX, and growth arrest- and DNA-damage inducible protein 153 via glycogen synthase kinase-3beta in ischemic-reperfused hearts. Hypertension. 2013;61(1):95–104. doi: 10.1161/HYPERTENSIONAHA.111.00028. CrossRefPubMed
Hoda MN, Siddiqui S, Herberg S, Periyasamy-Thandavan S, Bhatia K, Hafez SS, et al. Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type plasminogen activator in murine model of embolic stroke. Stroke. 2012;43(10):2794–9. doi: 10.1161/STROKEAHA.112.660373. CrossRefPubMedPubMedCentral
Meng R, Ding Y, Asmaro K, Brogan D, Meng L, Sui M, et al. Ischemic conditioning is safe and effective for octo- and nonagenarians in stroke prevention and treatment. Neurotherapeutics. 2015; doi: 10.1007/s13311-015-0358-6.
Ding Y, Li J, Luan X, Ding YH, Lai Q, Rafols JA, et al. Exercise pre-conditioning reduces brain damage in ischemic rats that may be associated with regional angiogenesis and cellular overexpression of neurotrophin. Neuroscience. 2004;124(3):583–91. doi: 10.1016/j.neuroscience.2003.12.029. CrossRefPubMed
Calvert JW, Condit ME, Aragon JP, Nicholson CK, Moody BF, Hood RL, et al. Exercise protects against myocardial ischemia-reperfusion injury via stimulation of beta(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols. Circ Res. 2011;108(12):1448–58. doi: 10.1161/CIRCRESAHA.111.241117. CrossRefPubMedPubMedCentral
Barbosa VA, Luciano TF, Marques SO, Vitto MF, Souza DR, Silva LA, et al. Acute exercise induce endothelial nitric oxide synthase phosphorylation via Akt and AMP-activated protein kinase in aorta of rats: role of reactive oxygen species. Int J Cardiol. 2013;167(6):2983–8. doi: 10.1016/j.ijcard.2012.08.050. CrossRefPubMed
- Chronic Remote Ischemic Conditioning Is Cerebroprotective and Induces Vascular Remodeling in a VCID Model
Mohammad Badruzzaman Khan
Md. Nasrul Hoda
Mohamed E. Awad
Jennifer L. Waller
David C. Hess
- Springer US