Implications of age-related changes in the blood-brain barrier for ischemic stroke and new treatment strategies

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Abstract

Ischemic strokes are prevalent across all age groups. Recent research has highlighted the importance of better understanding ischemia-induced damage of the blood-brain barrier (BBB) because it is related to both the severity of ischemic injury and neurological outcomes. The influence of advancing age on the structure and function of the BBB and the potential influence of these changes on ischemic stroke injury have received little consideration to date. Therefore, the present review outlines how ischemic injury influences the structure and function of the BBB at the anatomical, cellular, and molecular levels, and how these changes differ between adult and elderly populations with and without age-related comorbid diseases. This review further discusses how age-dependent changes and features of the BBB, and the corresponding alterations in response to ischemia, can affect the efficacy and delivery of current and future treatment options. Current research efforts are underway to develop prospective stroke treatment strategies that target the restoration of BBB functionality. This review also discusses the importance of considering the unique properties and characteristics of the BBB in elderly individuals for developing new stroke treatment strategies.

Keywords

Ischemic stroke

Blood-brain barrier

Inflammation

Drug delivery

Diabetes

Alzheimer’s disease

Funding

Canadian Institutes of Health Research

Conflict of interest

The authors declare no conflict of interests.

References

[1]

Erdö, F, Denes, L, De Lange, E, 2017, Age-associated physiological and pathological changes at the blood-brain barrier: A review. J Cereb Blood Flow Metab, 37: 4–24.

[2]

Latour LL, Kang DW, Ezzeddine MA, et al., 2004, Early blood-brain barrier disruption in human focal brain ischemia. Ann Neurol, 56: 468–477.

[3]

Bivard A, Kleinig T, Churilov L, et al., 2020, Permeability measures predict hemorrhagic transformation after ischemic stroke. Ann Neurol, 88: 466–476.

[4]

Brouns R, Wauters A, De Surgeloose D, et al., 2011, Biochemical markers for blood-brain barrier dysfunction in acute ischemic stroke correlate with evolution and outcome. Eur Neurol, 65: 23–31.

[5]

Daneman R, Prat A, 2015, The blood-brain barrier. Cold Spring Harb Perspect Biol, 7: a020412.

[6]

Abdullahi W, Tripathi D, Ronaldson PT, 2018, Blood-brain barrier dysfunction in ischemic stroke: Targeting tight junctions and transporters for vascular protection. Am J Physiol Cell Physiol, 315: C343–C356.

[7]

Jiang X, Andjelkovic AV, Zhu L, et al., 2018, Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol, 163–164: 144–171.

[8]

Kanji M, Atsuo F, Hajime T, et al., 1997, Vulnerability to cerebral hypoxic-ischemic insult in neonatal but not in adult rats is in parallel with disruption of the blood-brain barrier. Stroke, 28: 2281–2289.

[9]

DiNapoli VA, Huber JD, Houser K, et al., 2008, Early disruptions of the blood-brain barrier may contribute to exacerbated neuronal damage and prolonged functional recovery following stroke in aged rats. Neurobiol Aging, 29: 753–764.

[10]

Boot E, Ekker MS, Putaala J, et al., 2020, Ischaemic stroke in young adults: A global perspective. J Neurol Neurosurg Psychiatry, 91(4): 411–417.

[11]

Renna R, Pilato F, Profice P, et al., 2014, Risk factor and etiology analysis of ischemic stroke in young adult patients. J Stroke Cerebrovasc Dis, 23: e221–e227.

[12]

Tarja P, Timo E, Risto V, et al., 1997, Comparison of stroke features and disability in daily life in patients with ischemic stroke aged 55 to 70 and 71 to 85 years. Stroke, 28: 729–735.

[13]

Stack CA, Cole JW, 2018, Ischemic stroke in young adults. Curr Opin Cardiol, 33: 594–604.

[14]

Rojas JI, Zurrú MC, Romano M, et al., 2007, Acute ischemic stroke and transient ischemic attack in the very old-risk factor profile and stroke subtype between patients older than 80 years and patients aged less than 80 years. Eur J Neurol, 14: 895–899.

[15]

Arnold M, Halpern M, Meier N, et al., 2008, Age-dependent differences in demographics, risk factors, co-morbidity, etiology, management, and clinical outcome of acute ischemic stroke. J Neurol, 255(10): 1503–1507.

[16]

Chen RL, Balami JS, Esiri MM, et al., 2010, Ischemic stroke in the elderly: An overview of evidence. Nat Rev Neurol, 6: 256–265.

[17]

Ay H, Koroshetz WJ, Vangel M, et al., 2005, Conversion of ischemic brain tissue into infarction increases with age. Stroke, 36: 2632–2636.

[18]

Gokcay F, Arsava EM, Baykaner T, et al., 2011, Age-dependent susceptibility to infarct growth in women. Stroke, 42: 947–951.

[19]

Sengupta P, 2013, The laboratory rat: Relating its age with human’s. Int J Prev Med, 4: 624–630.

[20]

Bushnell CD, Lee J, Duncan PW, et al., 2008, Impact of comorbidities on ischemic stroke outcomes in women. Stroke, 39: 2138–2140.

[21]

Liu R, Wang H, Xu B, et al., 2016, Cerebrovascular safety of sulfonylureas: The role of KATPchannels in neuroprotection and the risk of stroke in patients with Type 2 diabetes. Diabetes, 65(9): 2795–2809.

[22]

Chi NF, Chien LN, Ku HL, et al., 2013, Alzheimer disease and risk of stroke: A population-based cohort study. Neurology, 80: 705–711.

[23]

Desmond DW, Moroney JT, Sano M, et al., 2022, Mortality in patients with dementia after ischemic stroke. Neurology, 59: 537–543.

[24]

Zhang F, Eckman C, Younkin S, et al., 1997. Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein. J Neurosci, 17: 7655–7661.

[25]

Szeto V, Chen N, Sun H, et al., 2018, The role of KATP channels in cerebral ischemic stroke and diabetes. Acta Pharmacol Sin, 39: 683–694.

[26]

Lin HB, Lin YH, Zhang JY, et al., 2021, NLRP3 inflammasome: A potential target in isoflurane pretreatment alleviates stroke-induced retinal injury in diabetes. Front Cell Neurosci, 15: 1–9.

[27]

Kuroiwa T, Ting P, Martinez H, et al., 1985, The biphasic opening of the blood-brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol, 68: 122–129.

[28]

Strbian D, Durukan A, Pitkonen M, et al., 2008, The blood-brain barrier is continuously open for several weeks following transient focal cerebral ischemia. Neuroscience, 153: 175–181.

[29]

Merali Z, Huang K, Mikulis D, et al., 2017, Evolution of blood-brain-barrier permeability after acute ischemic stroke. PLoS One, 12: 1–11.

[30]

Elahy M, Jackaman C, Cl Mamo J, et al., 2015, Blood-brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment. Immunol Ageing, 12: 1–9.

[31]

Kaur J, Tuor UI, Zhao Z, et al., 2011, Quantitative MRI reveals the elderly ischemic brain is susceptible to increased early blood-brain barrier permeability following tissue plasminogen activator related to claudin 5 and occludin disassembly. J Cereb Blood Flow Metab, 31: 1874–1885.

[32]

Zhang Z, Yan J, Shi H, 2016, Role of hypoxia inducible factor 1 in hyperglycemia-exacerbated blood-brain barrier disruption in ischemic stroke. Neurobiol Dis, 95: 82–92.

[33]

Hawkins BT, Lundeen TF, Norwood KM, et al., 2007, Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat: Contribution of hyperglycaemia and matrix metalloproteinases. Diabetologia, 50: 202–211.

[34]

Kumari R, Willing LB, Patel SD, et al., 2011, Increased cerebral matrix metalloprotease-9 activity is associated with compromised recovery in the diabetic db/db mouse following a stroke. J Neurochem, 119: 1029–1040.

[35]

Milner E, Zhou ML, Johnson AW, et al., 2014, Cerebral amyloid angiopathy increases susceptibility to infarction after focal cerebral ischemia in Tg2576 mice. Stroke, 45: 3064–3069.

[36]

Magaki S, Tang Z, Tung S, et al., 2018, The effects of cerebral amyloid angiopathy on integrity of the blood-brain barrier. Neurobiol. Aging, 70: 70–77.

[37]

Hartz AM, Bauer B, Soldner EL, et al., 2012, Amyloid-β contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy. Stroke, 43: 514–523.

[38]

Shen F, Jiang L, Han F, et al., 2018, Increased inflammatory response in old mice is associated with more severe neuronal injury at the acute stage of ischemic stroke. Aging Dis, 10: 12–22.

[39]

Elali A, Doeppner TR, Zechariah A, et al., 2011, Increased blood-brain barrier permeability and brain edema after focal cerebral ischemia induced by hyperlipidemia: Role of lipid peroxidation and calpain-1/2, matrix metalloproteinase-2/9, and rhoa overactivation. Stroke, 42: 3238–3244.

[40]

Huang YC, Feng ZP, 2013, The good and bad of microglia/ macrophages: New hope in stroke therapeutics. Acta Pharmacol Sin, 34: 6–7.

[41]

Ritzel RM, Lai YJ, Crapser JD, et al., 2018, Aging alters the immunological response to ischemic stroke. Acta Neuropathol, 136: 89–110.

[42]

Lee M, Lim JS, Kim CH, et al., 2021, High neutrophil-lymphocyte ratio predicts post-stroke cognitive impairment in acute ischemic stroke patients. Front Neurol, 12: 693318.

[43]

Kumari R, Bettermann K, Willing L, et al., 2020, The role of neutrophils in mediating stroke injury in the diabetic db/ db mouse brain following hypoxia-ischemia. Neurochem Int, 139: 104790.

[44]

Sayed A, Bahbah EI, Kamel S, et al., 2020, The neutrophil-to-lymphocyte ratio in Alzheimer’s disease: Current understanding and potential applications. J Neuroimmunol, 349: 577398.

[45]

Lakhan SE, Kirchgessner A, Tepper D, et al., 2013, Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke. Front Neurol, 4: 1–15.

[46]

Montaner J, Alvarez-Sabín J, Molina CA, et al., 2001, Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke, 32: 2762–2767.

[47]

Liu J, Jin X, Liu KJ, et al., 2012, Matrix metalloproteinase- 2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood-brain barrier damage in early ischemic stroke stage. J Neurosci, 32: 3044–3057.

[48]

Kamada H, Yu F, Nito C, et al., 2007, Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/ reperfusion in rats: Relation to blood-brain barrier dysfunction. Stroke, 38: 1044–1049.

[49]

Lasek-Bal A, Jedrzejowska-Szypulka H, Student S, et al., 2019, The importance of selected markers of inflammation and blood-brain barrier damage for short-term ischemic stroke prognosis. J Physiol Pharmacol, 70: 209–217.

[50]

Yang C, Hawkins KE, Doré S, et al., 2019, Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol, 316: C135–C153.

[51]

Pawluk H, Woźniak A, Grześk G, et al., 2020, The role of selected pro-inflammatory cytokines in pathogenesis of ischemic stroke. Clin Interv Aging, 15: 469–484.

[52]

Voirin AC, Perek N, Roche F, 2020, Inflammatory stress induced by a combination of cytokines (IL-6, IL-17, TNF-α) leads to a loss of integrity on bEnd.3 endothelial cells in vitro BBB model. Brain Res, 1730: 146647.

[53]

Dutta S, Sengupta P, 2016, Men and mice: Relating their ages. Life Sci, 152: 244–248.

[54]

Zhu W, Guo Z, Yu S, 2016, Higher neutrophil counts before thrombolysis for cerebral ischemia predict worse outcomes. Neurology, 86: 1077.

[55]

Inzitari D, Giusti B, Nencini P, et al., 2013, MMP9 variation after thrombolysis is associated with hemorrhagic transformation of lesion and death. Stroke, 44: 2901–2903.

[56]

Fan X, Qiu J, Yu Z, et al., 2012, A rat model of studying tissue-type plasminogen activator thrombolysis in ischemic stroke with diabetes. Stroke, 43: 567–570.

[57]

Umlauf BJ, Shusta EV, 2019, Exploiting BBB disruption for the delivery of nanocarriers to the diseased CNS. Curr Opin Biotechnol, 60: 146–152.

[58]

Dziedzic T, 2015, Systemic inflammation as a therapeutic target in acute ischemic stroke. Expert Rev Neurother, 15: 523–531.

[59]

Chaturvedi M, Kaczmarek L, 2014, MMP-9 inhibition: A therapeutic strategy in ischemic stroke. Mol Neurobiol, 49: 563–573.

[60]

Leonardo CC, Eakin AK, Ajmo JM, et al., 2008, Delayed administration of a matrix metalloproteinase inhibitor limits progressive brain injury after hypoxia-ischemia in the neonatal rat. J Neuroinflammation, 5: 1–11.

[61]

Leonardo CC, Pennypacker KR, 2009, Neuroinflammation and MMPs: Potential therapeutic targets in neonatal hypoxic-ischemic injury. J Neuroinflammation, 6: 1–7.

[62]

Leu S, Day YJ, Sun CK, et al., 2016, tPA-MMP-9 axis plays a pivotal role in mobilization of endothelial progenitor cells from bone marrow to circulation and Ischemic Region for angiogenesis. Stem Cells Int, 2016: 5417565.

[63]

Cai H, Ma Y, Jiang L, et al., 2017, Hypoxia response element-regulated MMP-9 promotes neurological recovery via glial scar degradation and angiogenesis in delayed stroke. Mol Ther, 25: 1448–1459.

[64]

DeMars KM, Yang C, Candelario-Jalil E, 2019, Neuroprotective effects of targeting BET proteins for degradation with dBET1 in aged mice subjected to ischemic stroke. Neurochem Int, 127: 94–102.

[65]

Weisenburger-Lile D, Dong Y, Yger M, et al., Harmful neutrophil subsets in patients with ischemic stroke. Neurol Neuroimmunol Neuroinflammation, 6: e571.

[66]

Murata Y, Rosell A, Scannevin RH, et al., 2008, Extension of the Thrombolytic time window with minocycline in experimental stroke. Stroke, 39: 3372–3377.

[67]

Boese AC, Eckert A, Hamblin MH, et al., 2020, Human neural stem cells improve early stage stroke outcome in delayed tissue plasminogen activator-treated aged stroke brains. Exp Neurol, 329: 113275.

[68]

Zhu S, Szeto V, Bao M, et al., 2018, Pharmacological approaches promoting stem cell-based therapy following ischemic stroke insults. Acta Pharmacol Sin, 39: 695–712.

[69]

Wu J, Sun Z, Sun HS, et al., Intravenously administered bone marrow cells migrate to damaged brain tissue and improve neural function in ischemic rats. Cell Transplant, 16: 993–1005.

[70]

Wang R, Zhu Y, Liu Z, et al., 2021, Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke. Blood, 138: 91–103.

[71]

Knecht T, Story J, Liu J, et al., 2017, Adjunctive therapy approaches for ischemic stroke: Innovations to expand time window of treatment. Int J Mol Sci, 18: 2756.

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