Sex differences in neuroinflammation and neuroprotection in ischemic stroke

Spychala, Monica S.; Honarpisheh, Pedram; McCullough, Louise D.

doi:10.1002/jnr.23962

Cited by 127Acute Ischemic Stroke ManagementNeuroinflammation and Neurodegeneration MechanismsSex and Gender in Healthcare

Sex differences in neuroinflammation and neuroprotection in ischemic stroke

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Spychala, Monica S., Honarpisheh, Pedram, McCullough, Louise D.·2017·Journal of Neuroscience Research

DOI 10.1002/jnr.23962PMC PMC5217708

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Abstract

Stroke is not only a leading cause of mortality and morbidity worldwide it also disproportionally affects women. There are currently over 500,000 more women stroke survivors in the US than men, and elderly women bear the brunt of stroke-related disability. Stroke has dropped to the fifth leading cause of death in men, but remains the third in women. This review discusses sex differences in common stroke risk factors, the efficacy of stroke prevention therapies, acute treatment responses, and post-stroke recovery in clinical populations. Women have an increased lifetime risk of stroke compared to men, largely due to a steep increase in stroke incidence in older postmenopausal women, yet most basic science studies continue to only evaluate young male animals. Women also have an increased lifetime prevalence of many common stroke risk factors, including hypertension and atrial fibrillation, as well as abdominal obesity and metabolic syndrome. None of these age-related risk factors have been well modeled in the laboratory. Evidence from the bench has implicated genetic and epigenetic factors, differential activation of cell-death programs, cell-cell signaling pathways, and systemic immune responses as contributors to sex differences in ischemic stroke. The most recent basic scientific findings have been summarized in this review, with an emphasis on factors that differ between males and females that are pertinent to stroke outcomes. Identification and understanding of the underlying biological factors that contribute to sex differences will be critical to the development of translational targets to improve the treatment of women after stroke. © 2016 Wiley Periodicals, Inc.

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Inducible Nitric Oxide Synthase Contributes to Gender Differences in Ischemic Brain Injury
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Systemic progesterone administration results in a partial reversal of the age‐associated decline in CNS remyelination following toxin‐induced demyelination in male rats
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An open-label evaluator-blinded clinical study of minocycline neuroprotection in ischemic stroke: gender-dependent effect
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Background
Sex Differences in Minocycline-Induced Neuroprotection after Experimental Stroke
Li, J., & McCullough, L. D. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2009.3 · Cited by 116 · cited 1× · see citing works
“In addition, as many androgens are aromatized to estrogen, the observed effects could be due to estrogen-mediated effects (Hurn, 2014; Li et al., 2011; Persky et al., 2013).”
Background
The importance of having two X chromosomes
Arnold, A. P., Reue, K., Eghbali, M., Vilain, E., Chen, X., Ghahramani, N., Itoh, Y., Li, J., Link, J. C., Ngun, T., et al. (2016) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2015.0113 · Cited by 114 · cited 2× · see citing works
“The development of the immune system occurs in the setting of the XX versus XY chromosomal background, with an additional contribution from gonadal hormones (Arnold et al., 2016; Fischer et al., 2015; Trigunaite et al., 2015).”
Background
Stroke sensitivity in the aged: sex chromosome complement vs. gonadal hormones
McCullough, L. D., Mirza, M. A., Xu, Y., Bentivegna, K., Steffens, E. B., Ritzel, R. M., & Liu, F. (2016) · Aging · doi:10.18632/aging.100997 · Cited by 114 · cited 4× · see citing works
“PARP induces a well-recognized programmed cell death involving neuronal nitric oxide synthase (nNOS), PARP-1, and apoptotic inducing factor (AIF).”
BackgroundInfluential
Racial and Gender Differences in Stroke Severity, Outcomes, and Treatment in Patients with Acute Ischemic Stroke
Boehme, A. K., Siegler, J. E., Mullen, M. T., Albright, K. C., Lyerly, M. J., Monlezun, D. J., Jones, E., Tanner, R. M., Gonzales, N. R., Beasley, T. M., et al. (2014) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2013.11.003 · Cited by 108 · cited 2× · see citing works
“Both types of damage vary by sex (Ahnstedt et al., 2016; Boehme et al., 2014; Crislip and Sullivan, 2016).”
Background
The Importance of Considering Sex Differences in Translational Stroke Research
Ahnstedt, H. W., McCullough, L. D., & Cipolla, M. J. (2016) · Translational Stroke Research · doi:10.1007/s12975-016-0450-1 · Cited by 107 · cited 2× · see citing works
“Both types of damage vary by sex (Ahnstedt et al., 2016; Boehme et al., 2014; Crislip and Sullivan, 2016).”
Background
The number of X chromosomes influences protection from cardiac ischaemia/reperfusion injury in mice: one X is better than two
Li, J., Chen, X., McClusky, R., Ruiz-Sundstrom, M., Itoh, Y., Umar, S., Arnold, A. P., & Eghbali, M. (2014) · Cardiovascular Research · doi:10.1093/cvr/cvu064 · Cited by 106 · cited 1× · see citing works
“Work in our lab has shown that minocycline does not protect overiectomized female mice despite having a robust effect in reducing the infarct size in male mice (Li and McCullough, 2009).”
Background
Gender-Specific Response to Isoflurane Preconditioning in Focal Cerebral Ischemia
Kitano, H., Young, J. M., Cheng, J., Wang, L., Hurn, P. D., & Murphy, S. J. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600444 · Cited by 93 · cited 3× · see citing works
“…(PARP) (Siffrin et al., 2010), nitric oxide synthase (NOS) (McCullough et al., 2005; Park et al., 2006), glutathione (Siffrin et al., 2010), Akt (Kitano et al., 2007), astrocytic aromatase (Liu et al., 2007), glial fibrillary acidic protein (GFAP) (Cordeau et al., 2008), angiotensin II type 2…”
Background
Epigenetics and sex differences in the brain: A genome-wide comparison of histone-3 lysine-4 trimethylation (H3K4me3) in male and female mice
Shen, E., Ahern, T. H., Cheung, I. K., Straubhaar, J., Dincer, A., Houston, I. B., Vries, G. J. D., Akbarian, S., & Forger, N. G. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.08.006 · Cited by 91 · cited 3× · see citing works
“At the baseline conditions however, only a minority of genes with a sex difference in H3K4me3 showed detectable sex differences in expression (Shen et al., 2015).”
BackgroundMethodInfluential
Role of Soluble Epoxide Hydrolase in the Sex-Specific Vascular Response to Cerebral Ischemia
Zhang, W. H., Iliff, J. J., Campbell, C. J., Wang, R. K., Hurn, P. D., & Alkayed, N. J. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2009.65 · Cited by 86 · cited 2× · see citing works
“, 2009), and the soluble epoxide hydrolase (sEH) (Zhang et al., 2009).”
Background
Interactions between age, sex, and hormones in experimental ischemic stroke
Liu, F., & McCullough, L. D. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.10.003 · Cited by 84 · cited 1× · see citing works
“…synthase (NOS) (McCullough et al., 2005; Park et al., 2006), glutathione (Siffrin et al., 2010), Akt (Kitano et al., 2007), astrocytic aromatase (Liu et al., 2007), glial fibrillary acidic protein (GFAP) (Cordeau et al., 2008), angiotensin II type 2 receptor (Sakata et al., 2009), and the…”
Background
Histone methylation patterns in astrocytes are influenced by age following ischemia
Chisholm, N. C., Henderson, M. L., Selvamani, A., Park, M. J., Dindot, S. V., Miranda, R. C., & Sohrabji, F. (2015) · Epigenetics · doi:10.1080/15592294.2014.1001219 · Cited by 73 · see citing works
Age-related changes in brain support cells: Implications for stroke severity
Sohrabji, F., Bake, S., & Lewis, D. K. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.06.013 · Cited by 70 · cited 2× · see citing works
“5 higher rates of nursing home placement compared to male stroke survivors (Gargano et al., 2007; Lai et al., 2005; Sohrabji et al., 2013; Writing Group et al., 2016).”
BackgroundInfluential
Phenotypic Changes in Immune Cell Subsets Reflect Increased Infarct Volume in Male vs. Female Mice
Banerjee, A., Wang, J., Bodhankar, S., Vandenbark, A. A., Murphy, S. J., & Offner, H. (2013) · Translational Stroke Research · doi:10.1007/s12975-013-0268-z · Cited by 68 · cited 1× · see citing works
“Similar but sex-specific results have been observed in murine models where female mice show an increase in a subset of IL-10 secreting CD81 T cells after stroke, which is not seen in male mice (Banerjee et al., 2013).”
Result
Effects of Chronic and Acute Oestrogen Replacement Therapy in Aged Animals after Experimental Stroke
Liu, F., Benashski, S. E., Xu, Y., Siegel, M., & McCullough, L. D. (2011) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2011.02248.x · Cited by 54 · cited 8× · see citing works
“…the variation in ischemic sensitivity across the lifespan, research efforts with a focus on sex differences in neuronal cell death signaling, immune responses, and inflammation have recently received more attention (Klein et al., 2015; Liu et al., 2009; Manwani et al., 2013; Mirza et al., 2015).”
BackgroundResultInfluential
Sex-different effect of angiotensin II type 2 receptor on ischemic brain injury and cognitive function
Sakata, A., Mogi, M., Iwanami, J., Tsukuda, K., Min, L., Fujita, T., Iwai, M., Ito, M., & Horiuchi, M. (2009) · Brain Research · doi:10.1016/j.brainres.2009.08.068 · Cited by 51 · cited 2× · see citing works
“, 2008), angiotensin II type 2 receptor (Sakata et al., 2009), and the soluble epoxide hydrolase (sEH) (Zhang et al.”
Background
NAD+ and Nicotinamide: Sex Differences in Cerebral Ischemia
Siegel, C. S., & McCullough, L. D. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.01.068 · Cited by 41 · cited 1× · see citing works
“Treatment with nicotinamide preferentially protects males while it shows minimal benefits in the wild-type female mice (Siegel and McCullough, 2013), however clinical trials rarely evaluate men and women independently.”
Background
Sexual dimorphism in cerebral ischemia injury
Zuo, W., Zhang, W., & Chen, N. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.04.024 · Cited by 41 · cited 2× · see citing works
“In bench studies that controlled for androgen levels, the data seem conflicting and indicate that androgens can either protect or exacerbate ischemic damage (Zuo et al., 2013).”
Background
Histone Methyltransferase and Histone Methylation in Inflammatory T-Cell Responses
He, S., Tong, Q., Bishop, D. K., & Zhang, Y. (2013) · Immunotherapy · doi:10.2217/imt.13.101 · Cited by 40 · cited 2× · see citing works
“Histone methylation signatures have been correlated with regulation of transcriptional programs in effector and memory T cells (He et al., 2013) and the overall response following ischemic stroke (Chisholm et al.”
Background
Difference in the Immunoglobulin Class of Polioantibody in the Serum of Men and Women
Ainbender, E., Weisinger, R. B., Hevizy, M., & Hodes, H. L. (1968) · The Journal of Immunology · doi:10.4049/jimmunol.101.1.92 · Cited by 39 · cited 1× · see citing works
“For example, vaccine-triggered antibody responses to diverse list of vaccines including the polio vaccine, the influenza vaccine, and the yellow fever virus vaccine are different in men and women (Ainbender et al., 1968; Furman et al., 2014; Klein et al., 2015).”
Background
Sex differences and the role of IL-10 in ischemic stroke recovery
Conway, S. E., Roy-O’Reilly, M. A., Friedler, B. D., Staff, I., Fortunato, G., & McCullough, L. D. (2015) · Biology of Sex Differences · doi:10.1186/s13293-015-0035-9 · Cited by 37 · cited 1× · see citing works
“In ischemic stroke, an excessive IL-10 response contributes to post-stroke immunosuppression, which is known to worsen outcomes in terms of recovery (Conway et al., 2015).”
Background
Sex shapes experimental ischemic brain injury
Cheng, J. G., & Hurn, P. D. (2009) · Steroids · doi:10.1016/j.steroids.2009.10.014 · Cited by 33 · see citing works
The poly(ADP-ribose) polymerase 1 interacts with Sry and modulates its biological functions
Li, Y., Oh, H. J., & Lau, Y. C. (2006) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2006.06.008 · Cited by 32 · cited 1× · see citing works
“The results show that the reduction in PAR polymer formation is not different in males and females given minocycline, suggesting a non-linear relationship between PAR polymer and infarct size, at least in females (Li et al., 2006).”
Background
T-cell involvement in sex differences in blood pressure control
Crislip, G. R., & Sullivan, J. C. (2016) · Clinical Science · doi:10.1042/cs20150620 · Cited by 32 · see citing works
Progesterone for Neuroprotection in Pediatric Traumatic Brain Injury
Robertson, C., Fidan, E., Stanley, R. M., Noje, C., & Bayır, H. (2015) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0000000000000323 · Cited by 27 · cited 1× · see citing works
“As another example, progesterone reduces levels of pro-inflammatory cytokines (Robertson et al., 2015).”
Background
Gr1+ Cells Suppress T-Dependent Antibody Responses in (NZB × NZW)F1 Male Mice through Inhibition of T Follicular Helper Cells and Germinal Center Formation
Der, E. B., Dimo, J., Trigunaite, A., Jones, J., & Jørgensen, T. N. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302479 · Cited by 23 · cited 1× · see citing works
“Sex differences have also been well documented in autoimmune diseases such as lupus, where incidence rates are drastically higher in women (Der et al., 2014; Trigunaite et al., 2015).”
Background
Neonatal Testosterone Exposure Protects Adult Male Rats from Stroke
Persky, R., Liu, F., Xu, Y., Weston, G. K., Levy, S. J., Roselli, C. E., & McCullough, L. D. (2012) · Neuroendocrinology · doi:10.1159/000343804 · Cited by 22 · cited 1× · see citing works
“In addition, as many androgens are aromatized to estrogen, the observed effects could be due to estrogen-mediated effects (Hurn, 2014; Li et al., 2011; Persky et al., 2013).”
Background
Systemic Transcriptional Alterations of Innate and Adaptive Immune Signaling Pathways in Atherosclerosis, Ischemia Stroke, and Myocardial Infarction
Barr, T. L. (2015) · Journal of Bioanalysis & Biomedicine · doi:10.4172/1948-593x.1000120 · Cited by 20 · cited 1× · see citing works
“Thus, epigenetic regulations may contribute to the coordinated response of innate and adaptive immunity in ischemic stroke and some other atherosclerotic diseases (Barr et al., 2015).”
Background
‘Sex, neuroprotection, and neonatal ischemia’
Renolleau, S., Fau, S., Goyenvalle, C., & Charriaut‐Marlangue, C. (2007) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.2007.00477.x · Cited by 16 · cited 2× · see citing works
“Work in our lab and by other research groups has demonstrated sex differences in ischemiainduced cell death pathways in young, adult, and aged animals (Hagberg et al., 2004; Liu et al., 2009; Renolleau et al., 2007a).”
Result
2014 Thomas Willis Award Lecture
Hurn, P. D. (2014) · Stroke · doi:10.1161/strokeaha.114.005377 · Cited by 14 · cited 1× · see citing works
“In addition, as many androgens are aromatized to estrogen, the observed effects could be due to estrogen-mediated effects (Hurn, 2014; Li et al., 2011; Persky et al., 2013).”
Background
Sex-Related Immune Changes in Young Mice
Rosen, J. L., Tran, H. T., Lackey, A., & Viselli, S. M. (1999) · Immunological Investigations · doi:10.3109/08820139909060859 · Cited by 11 · cited 2× · see citing works
“The response to stroke is sexually dimorphic even in neonatal models, suggesting that changes are Journal of Neuroscience Research patterned early in development and are in part, independent of the activational effects of gonadal hormones (Hagberg et al., 2004; Rosen et al., 1999).”
Background

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Sex-specific features of microglia from adult mice
Villa, A., Gelosa, P., Castiglioni, L., Cimino, M., Rizzi, N., Pepe, G., Lolli, F., Marcello, E., Sironi, L., Vegeto, E., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.05.048 · Cited by 651 · see citing works
“Several authors demonstrated that in the case of forebrain or focal ischemia, young adult female rodents sustain smaller injury than males, and females have lower mortality than males (Murphy et al., 2004; Spychala et al., 2017).”
BackgroundResult
Sex Differences in Acute Neuroinflammation after Experimental Traumatic Brain Injury Are Mediated by Infiltrating Myeloid Cells
Doran, S. J., Ritzel, R., Glaser, E. P., Henry, R., Faden, A., & Loane, D. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2018.6019 · Cited by 154 · see citing works
“stroke field implicate peripherally derived immune cells in sex differences for infarct volume, neuronal cell death and secondary neuroinflammation.(11,46) For example, adult female mice exhibited a decrease in infiltrating and activated monocytes/microglia in the”
Background
Aging Microbiota-Gut-Brain Axis in Stroke Risk and Outcome
Honarpisheh, P., Bryan, R. M., & McCullough, L. D. (2022) · Circulation Research · doi:10.1161/circresaha.122.319983 · Cited by 173 · see citing works
Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?
Stuckey, S. M., Ong, L. K., Collins‐Praino, L. E., & Turner, R. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313101 · Cited by 157 · see citing works
“Moreover, evidence has suggested that, post-stroke, the innate cellular differences between males and females allow females to tolerate cellular stress and resist inflammation-induced cell death longer than their male counterparts [310].”
Background
Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine
Lynch, M. A. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.868448 · Cited by 146 · see citing works
Sex differences and the endocannabinoid system in pain
Blanton, H. L., Barnes, R. C., McHann, M. C., Bilbrey, J. A., Wilkerson, J. L., & Guindon, J. (2021) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2021.173107 · Cited by 143 · see citing works
“Neuroimmune-mediated neuroinflammation has been demonstrated to both directly induce pain and to contribute to sensitization in chronic pain, with noted sex differences in the functioning of this system (Ji et al., 2018; Rosen et al., 2017; Spychala et al., 2017).”
Background
Astrocyte-Derived Estrogen Regulates Reactive Astrogliosis and is Neuroprotective following Ischemic Brain Injury
Wang, J., Sareddy, G. R., Lu, Y., Pratap, U. P., Tang, F., Greene, K. M., Meyre, P. L., TEKMAL, R. R., Vadlamudi, R. K., & Brann, D. W. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.0888-20.2020 · Cited by 125 · see citing works
“For instance, previous studies have provided evidence that gender differences exist in cell death signaling, immune response, and recovery following cerebral ischemia (Spychala et al., 2017).”
Background
Heart–brain interactions in cardiac and brain diseases: why sex matters
Rossi, A., Mikaïl, N., Bengs, S., Haider, A., Treyer, V., Buechel, R. R., Wegener, S., Rauen, K., Tawakol, A. A., Merz, C. N. B., et al. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac061 · Cited by 116 · see citing works
Understanding Traumatic Brain Injury in Females: A State-of-the-Art Summary and Future Directions
Valera, E. M., Joseph, A.-L. C., Snedaker, K., Breiding, M. J., Robertson, C., Colantonio, A., Levin, H. S., Pugh, M. J., Yurgelun-Todd, D. A., Mannix, R., et al. (2020) · Journal of Head Trauma Rehabilitation · doi:10.1097/htr.0000000000000652 · Cited by 113 · see citing works
Effect of Caffeine Consumption on the Risk for Neurological and Psychiatric Disorders: Sex Differences in Human
Jee, H. J., Lee, S. G., Bormate, K. J., & Jung, Y.-S. (2020) · Nutrients · doi:10.3390/nu12103080 · Cited by 111 · see citing works
“According to a paper published in British Medical Journal (BMJ) in 2017, drinking 3–4 cups of coffee per day is associated with a reduced risk of various neurological disorders, including AD, PD, and depression [90].”
Method
Anti-inflammatory treatments for stroke: from bench to bedside
Drieu, A., Levard, D., Vivien, D., & Rubio, M. (2018) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756286418789854 · Cited by 101 · see citing works
The Translational Potential of Microglia and Monocyte-Derived Macrophages in Ischemic Stroke
Wicks, E. E., Ran, K. R., Kim, J. E., Xu, R., Lee, R. P., & Jackson, C. M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.897022 · Cited by 92 · see citing works
“Mouse model studies have demonstrated that resting state male microglia exhibit higher expression of inflammatory genes regulated by the NF-kb transcription factor compared to female microglia, and male mice subjected to cerebral ischemia developed larger infarcts than female mice (89, 90) The difference in infarct si…”
Background
Priming of Adult Incision Response by Early-Life Injury: Neonatal Microglial Inhibition Has Persistent But Sexually Dimorphic Effects in Adult Rats
Moriarty, O., Tu, Y., Sengar, A. S., Salter, M. W., Beggs, S., & Walker, S. M. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.1786-18.2019 · Cited by 75 · see citing works
“…inhibition with minocycline has also been variably reported to have no benefit (Cikla et al., 2016), paradoxically increase acute cell death (Strahan et al., 2017) and worsen longterm function (Hanlon et al., 2017), or improve outcome (Wixey et al., 2011; Schmitz et al., 2014), depending on…”
Background
Transcriptional activation of antioxidant gene expression by Nrf2 protects against mitochondrial dysfunction and neuronal death associated with acute and chronic neurodegeneration
Goodfellow, M. J., Borcar, A., Proctor, J. L., Greco, T., Rosenthal, R. E., & Fiskum, G. M. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113247 · Cited by 74 · see citing works
Sex differences in the inflammatory response to stroke
Tariq, M. B., Lee, J., & McCullough, L. D. (2022) · Seminars in Immunopathology · doi:10.1007/s00281-022-00969-x · Cited by 70 · see citing works
“These differences may account for post-stroke morbidity, and hence, identification of these disparities is important to stroke management and drug development [20].”
Background
Gender Differences in Oxidative Stress in Relation to Cancer Susceptibility and Survival
Allegra, A., Caserta, S., Genovese, S., Pioggia, G., & Gangemi, S. (2023) · Antioxidants · doi:10.3390/antiox12061255 · Cited by 68 · see citing works
Sex-specific cognitive deficits following space radiation exposure
Parihar, V. K., Angulo, M. C., Allen, B. D., Syage, A., Usmani, M. T., Passerat de la Chapelle, E., Amin, A. N., Flores, L., Lin, X., Giedzinski, E., et al. (2020) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2020.535885 · Cited by 67 · see citing works
Sexual hormones regulate the redox status and mitochondrial function in the brain. Pathological implications
Torrens‐Mas, M., Pons, D. G., Sastre‐Serra, J., Oliver, J., & Roca, P. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101505 · Cited by 65 · see citing works
Predictors of malignant cerebral edema in cerebral artery infarction: A meta-analysis
Miao, J., Song, X., Sun, W., Qiu, X., Lan, Y., & Zhou, Z. (2019) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2019.116607 · Cited by 52 · see citing works
Sex-Specific Differences in Redox Homeostasis in Brain Norm and Disease
Ruszkiewicz, J. A., Miranda‐Vizuete, A., Tinkov, A. A., Геннадиевна, С. М., Skalny, A. V., Tsatsakis, A. M., & Aschner, M. (2019) · Journal of Molecular Neuroscience · doi:10.1007/s12031-018-1241-9 · Cited by 47 · see citing works
Equitable modelling of brain imaging by counterfactual augmentation with morphologically constrained 3D deep generative models
Pombo, G., Gray, R., Cardoso, M. J., Sebastien Ourselin, A., Rees, G. E., Ashburner, J., & Nachev, P. (2022) · Medical Image Analysis · doi:10.1016/j.media.2022.102723 · Cited by 48 · see citing works
Estrogen receptor beta modulates permeability transition in brain mitochondria
Burstein, S. R., Kim, H. J., Fels, J. A., Qian, L., Zhang, S., Zhou, P., Starkov, A. A., Iadecola, C., & Manfredi, G. (2018) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2018.03.006 · Cited by 48 · see citing works
“Furthermore, recent studies have highlighted cellular mechanisms, which differ between males and females, that may contribute to sex differences in stroke incidence and outcome [3].”
Background
Stroke in women: When gender matters
Thomas, Q., Crespy, V., Duloquin, G., Ndiaye, M., Sauvant, M., Béjot, Y., & Giroud, M. (2021) · Revue Neurologique · doi:10.1016/j.neurol.2021.01.012 · Cited by 48 · see citing works
The Canadian Women’s Heart Health Alliance Atlas on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women — Chapter 5: Sex- and Gender-Unique Manifestations of Cardiovascular Disease
Pacheco, C., Mullen, K., Coutinho, T. A., Jaffer, S., Parry, M. J. E., Spall, H. G. C. V., Clavel, M.-A. A., Edwards, J. D., Sedlak, T., Norris, C. M., et al. (2021) · CJC Open · doi:10.1016/j.cjco.2021.11.006 · Cited by 48 · see citing works
“Differences in genetic factors and differential activation of apoptotic cell-cell signalling pathways and neuroinflammatory and immune responses might contribute to sex differences in stroke risk.(220)”
Background
Sex Differences in Ischemia/Reperfusion Injury: The Role of Mitochondrial Permeability Transition
Fels, J. A., & Manfredi, G. (2019) · Neurochemical Research · doi:10.1007/s11064-019-02769-6 · Cited by 45 · see citing works
“5 times more likely to be placed in a nursing home post-stroke than men [3].”
BackgroundInfluential
Can quantifying morphology and TMEM119 expression distinguish between microglia and infiltrating macrophages after ischemic stroke and reperfusion in male and female mice?
Young, K., Gardner, R., Sariana, V., Whitman, S. A., Bartlett, M. J., Falk, T., & Morrison, H. W. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02105-2 · Cited by 43 · see citing works
Sex as a biological variable in the pathology and pharmacology of neurodegenerative and neurovascular diseases
Honarpisheh, P., & McCullough, L. D. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14675 · Cited by 38 · see citing works
Ischemic stroke across sexes: What is the status quo?
Liberale, L., Carbone, F., Montecucco, F., Gebhard, C., Lüscher, T. F., Wegener, S., & Camici, G. G. (2018) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2018.05.001 · Cited by 37 · see citing works
Chromosomal and environmental contributions to sex differences in the vulnerability to neurological and neuropsychiatric disorders: Implications for therapeutic interventions
Pallier, P. N., Ferrara, M., Romagnolo, F., Ferretti, M. T., Soreq, H., & Cerase, A. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102353 · Cited by 35 · see citing works
Impact of sex on neuroimmune contributions to Parkinson’s disease
Bourque, M., Morissette, M., Soulet, D., & Paolo, T. D. (2023) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.110668 · Cited by 34 · see citing works
“Moreover, in a mice model of cerebral ischemia where the damage is generally greater in males compared to females (Spychala et al., 2017), transplantation of male”
Background
Gut–Brain Axis: Focus on Sex Differences in Neuroinflammation
Caldarelli, M., Rio, P., Marrone, A., Ocarino, F., Chiantore, M., Candelli, M., Gasbarrini, A., Gambassi, G., & Cianci, R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25105377 · Cited by 36 · see citing works
“The mechanisms through which this occurs represent the starting point for a different management of the disease and the development of therapeutic interventions [117].”
Background
Sex differences in the effects of PARP inhibition on microglial phenotypes following neonatal stroke
Charriaut‐Marlangue, C., Leconte, C., Csaba, Z., Chafa, L., Pansiot, J., Talatizi, M., Simon, K., Moretti, R., Marchand‐Leroux, C., Baud, O., et al. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.05.022 · Cited by 33 · see citing works
Absent Cortical Venous Filling Is Associated with Aggravated Brain Edema in Acute Ischemic Stroke
Xia, H., Sun, H., He, S., Zhao, M., Huang, W., Zhang, Z., Xue, Y., Fu, P., & Chen, W. (2021) · American Journal of Neuroradiology · doi:10.3174/ajnr.a7039 · Cited by 34 · see citing works
Sex-Associated Differences in Neurovascular Dysfunction During Ischemic Stroke
Tang, T., Hu, L., Liu, Y., Fu, X., Li, J., Yan, F., Cao, S., & Chen, G. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.860959 · Cited by 33 · see citing works
Sex-specific differences in organic anion transporting polypeptide 1a4 (Oatp1a4) functional expression at the blood–brain barrier in Sprague–Dawley rats
Brzica, H., Abdullahi, W., Reilly, B. G., & Ronaldson, P. T. (2018) · Fluids and Barriers of the CNS · doi:10.1186/s12987-018-0110-9 · Cited by 33 · see citing works
Leukocyte Count and Adverse Clinical Outcomes in Acute Ischemic Stroke Patients
Quan, K., Wang, A., Zhang, X., & Wang, Y. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01240 · Cited by 32 · see citing works
Neurosteroids: A novel promise for the treatment of stroke and post‐stroke complications
Xu, J., Zhou, Y., Yan, C., Wang, X., Lou, J., Luo, Y., Gao, S., Wang, J., Wu, L., Gao, X., et al. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15503 · Cited by 31 · see citing works
In a stroke cohort with incident hypertension; are more women than men likely to be excluded from recombinant tissue-type Plasminogen Activator (rtPA)?
Gainey, J. C., Brechtel, L. E., Konklin, S., Madeline, L. A., Lowther, E. L., Blum, B., & Nathaniel, T. I. (2018) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2018.02.016 · Cited by 30 · see citing works
NF-κB p65 directs sex-specific neuroprotection in human neurons
Ruiz-Perera, L. M., Schneider, L. V., Windmöller, B. A., Müller, J., Greiner, J. F. W., Kaltschmidt, C., & Kaltschmidt, B. (2018) · Scientific Reports · doi:10.1038/s41598-018-34394-8 · Cited by 28 · see citing works
Natural neuroprotective alkaloids from Stephania japonica (Thunb.) Miers
Xiao, J., Hao, T., Chen, G., Song, J., Lin, B., Li, W., Xu, J., Liu, J., Hou, Y., & Li, N. (2019) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2019.103175 · Cited by 28 · see citing works
“Stroke remains one of the leading causes of death and disability, being the 3rd leading cause of death in women and the 5th leading cause of death in men in the United States [1].”
Background
Clinical impact of estradiol/testosterone ratio in patients with acute ischemic stroke
Choi, J. W., Ryoo, I. W., Hong, J. Y., Lee, K., Nam, H. S., Kim, W. C., Oh, S.-H., Kang, J., Lee, H. Y., Na, S.-J., et al. (2021) · BMC Neurology · doi:10.1186/s12883-021-02116-9 · Cited by 28 · see citing works
Bacterial Amyloid Curli Associated Gut Epithelial Neuroendocrine Activation Predominantly Observed in Alzheimer’s Disease Mice with Central Amyloid-β Pathology
Das, T. K., Blasco-Conesa, M. P., Korf, J. M., Honarpisheh, P., Chapman, M. R., & Ganesh, B. P. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220106 · Cited by 28 · see citing works
“Age-related alterations in the gut microbiota composition have been documented, with decreased bacterial diversity and stability [3, 4].”
Influential
Between mind and heart: Sex-based cognitive bias in cardiovascular disease treatment
Kentner, A. C., & Grace, S. L. (2017) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2017.02.002 · Cited by 28 · see citing works
Associations between sex, body mass index and the individual microglial response in Alzheimer’s disease
Biechele, G., Rauchmann, B., Janowitz, D., Büerger, K., Franzmeier, N., Weidinger, E., Guersel, S., Schuster, S., Finze, A., Harris, S., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03020-y · Cited by 27 · see citing works
“It is further demonstrated, that female rodents better sustain injury after focal ischemia than male mice [44], possibly due to neurotrophic factors generated by microglia, that are beneficial for neuronal plasticity [45].”
Background
Sexual dimorphism in immune cell responses following stroke
Liu, J., Satō, Y., Falcone-Juengert, J., Kurisu, K., Shi, J., & Yenari, M. A. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105836 · Cited by 26 · see citing works
“As previously described, immune cells play a critical role in the pathology of ischemic stroke (Spychala et al., 2017).”
Antineuroinflammation of Minocycline in Stroke
Chen, Y., Cai, Z., & Ke, Z. (2017) · The Neurologist · doi:10.1097/nrl.0000000000000136 · Cited by 27 · see citing works
Estradiol Protects White Matter of Male C57BL6J Mice against Experimental Chronic Cerebral Hypoperfusion
Dominguez, R., Zitting, M., Liu, Q., Patel, A. B., Babadjouni, R., Hodis, D. M., Chow, R. H., & Mack, W. J. (2018) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2018.01.030 · Cited by 26 · see citing works
Estradiol mediates colonic epithelial protection in aged mice after stroke and is associated with shifts in the gut microbiome
Lee, J., Peesh, P., Quaicoe, V. A., Tan, C., Banerjee, A., Mooz, P., Ganesh, B. P., Petrosino, J. F., Bryan, R. M., McCullough, L. D., et al. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2271629 · Cited by 26 · see citing works
Gender differences in mortality of hospitalised stroke patients. Systematic review and meta-analysis
Abdel-Fattah, A.-R., Pana, T. A., Smith, T. O., Pasdar, Z., Aslam, M., Mamas, M. A., & Myint, P. K. (2022) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2022.107359 · Cited by 24 · see citing works
“neuroprotection offered by higher levels of oestrogen in women as well as slowing large artery atherosclerosis build-up.([46]) Although these studies suggest women have less severe strokes, it is important to highlight that lack of adjustment for stroke subtype, severity and”
Revealing sex-specific molecular changes in hypoxia-ischemia induced neural damage and subsequent recovery using zebrafish model
Das, T., Soren, K., Yerasi, M., Kumar, A., & Chakravarty, S. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134492 · Cited by 23 · see citing works
Dexmedetomidine Restores Autophagic Flux, Modulates Associated microRNAs and the Cholinergic Anti-inflammatory Pathway upon LPS-Treatment in Rats
Kho, W., von Haefen, C., Paeschke, N., Nasser, F., Endesfelder, S., Sifringer, M., González-López, A., Lanzke, N., & Spies, C. (2021) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-021-10003-w · Cited by 23 · see citing works
Influence of Sex on Stroke Prognosis: A Demographic, Clinical, and Molecular Analysis
Castro, E. R., Rodríguez‐Yáñez, M., Arias, S., Santamaría, M., López‐Dequidt, I., López-Loureiro, I., Rodríguez-Pérez, M., Hervella, P., Sobrino, T., Campos, F., et al. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00388 · Cited by 23 · see citing works
Sexual Dimorphism in Neurodegenerative Diseases and in Brain Ischemia
Zalewska, T., Pawelec, P., Ziąbska, K., & Ziemka‐Nałęcz, M. (2022) · Biomolecules · doi:10.3390/biom13010026 · Cited by 22 · see citing works
Interaction of Sex and Diabetes on Outcome After Ischemic Stroke
Soriano-Reixach, M. M., Vivanco‐Hidalgo, R. M., Ois, Á., Rodríguez-Campello, A., & Roquer, J. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00250 · Cited by 22 · see citing works
“Other risk factors mainly affecting women have been described, such as relative longevity and sex-specific immune response and hormones (32, 33).”
Background
Elucidating sex differences in response to cerebral ischemia: immunoregulatory mechanisms and the role of microRNAs
Kaidonis, G., Rao, A. N., Ouyang, Y., & Stary, C. M. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.08.001 · Cited by 22 · see citing works
“The dose of estrogen that T helper cells are exposed to is also important in modulating their fate as either Th1 or Th2 cells, with low doses of estrogen favoring a pro-inflammatory Th1 response (Spychala et al., 2017).”
Immune regulation based on sex differences in ischemic stroke pathology
Niu, P., Li, L., Zhang, Y., Su, Z., Wang, B., Liu, H., Zhang, S., Qiu, S., & Li, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1087815 · Cited by 20 · see citing works
“Male microglia are more active and have a more proinflammatory phenotype (11, 54, 197) because they express higher amounts of Iba1, TLR2, and TLR4.”
Background
Role of age and neuroinflammation in the mechanism of cognitive deficits in sickle cell disease
Hardy, R. A., Rached, N. A., Jones, J. A., Archer, D. R., & Hyacinth, H. I. (2020) · Experimental Biology and Medicine · doi:10.1177/1535370220958011 · Cited by 21 · see citing works
Sexual dimorphisms in adult human neural, mesoderm‐derived, and neural crest‐derived stem cells
Greiner, J. F. W., Merten, M., Kaltschmidt, C., & Kaltschmidt, B. (2019) · FEBS Letters · doi:10.1002/1873-3468.13606 · Cited by 19 · see citing works
cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice
Shvedova, M., Litvak, M. M., Roberts, J. D., Fukumura, D., Suzuki, T., Şencan, İ., Li, G., Reventún, P., Buys, E. S., Kim, H.-H., et al. (2019) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x19870583 · Cited by 18 · see citing works
Current View on PPAR-α and Its Relation to Neurosteroids in Alzheimer’s Disease and Other Neuropsychiatric Disorders: Promising Targets in a Therapeutic Strategy
Żulińska, S., Strosznajder, A. K., & Strosznajder, J. B. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25137106 · Cited by 17 · see citing works
“Sex differences in immunity have been reported many years ago but the etiology is not yet exactly understood [77–81].”
Background
Peripherally-sourced myeloid antigen presenting cells increase with advanced aging
Honarpisheh, P., Blixt, F. W., Conesa, M. P. B., Won, W. W., d’Aigle, J., Munshi, Y., Hudobenko, J., Furr, J. W., Mobley, A. S., Lee, J., et al. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.08.023 · Cited by 17 · see citing works
“age as a biological variable, sex differences in the immune response contribute to sexually dimorphic incidence rates of autoimmune disorders, neurodegenerative and cerebrovascular diseases(Honarpisheh and McCullough, 2019; Klein and Flanagan, 2016; Spychala et al., 2017).”
Background
Sex differences in risk factors for stroke in patients with hypertension and hyperhomocysteinemia
Pang, H., Fu, Q., Cao, Q., Hao, L., & Zong, Z. (2019) · Scientific Reports · doi:10.1038/s41598-019-50856-z · Cited by 16 · see citing works
Antibody Protection against Long-Term Memory Loss Induced by Monomeric C-Reactive Protein in a Mouse Model of Dementia
García-Lara, E., Aguirre, S., Clotet, N., Sawkulycz, X., Bartra, C., Almenara‐Fuentes, L., Sunol, C. E., Corpas, R., Olah, P., Tripon, F., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9070828 · Cited by 16 · see citing works
“Sustained neuroinflammation is a risk factor for age-related diseases, including cerebrovascular injuries and Alzheimer’s disease (AD) [1,2].”
Background
Frontal Metabolites and Alzheimer’s Disease Biomarkers in Healthy Older Women and Women Diagnosed with Mild Cognitive Impairment
Hone‐Blanchet, A., Bohsali, A. A., Krishnamurthy, L. C., Shahid, S. S., Lin, Q., Zhao, L., Bisht, A. S., John, S. E., Loring, D. W., Goldstein, F. C., et al. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-215431 · Cited by 14 · see citing works
Necrosis Contributes to the Development of Hypertension in Male, but Not Female, Spontaneously Hypertensive Rats
Abdelbary, M. A., Rafikova, O., Gillis, E. E., Musall, J. B., Baban, B., O'Connor, P. M., Brands, M. W., & Sullivan, J. C. (2019) · Hypertension · doi:10.1161/hypertensionaha.119.13477 · Cited by 14 · see citing works
“Although not extensively studied in hypertension, there is considerable interest in the sex-specific roles of cell death in injury and recovery following stroke where males have greater levels of necrotic cell death compared with females.(7,8) Sex differences in cell death pathways have also been reported in cell cult…”
Background
Astrocytic YAP prevents the glutamate neurotoxicity by upregulation of EAAT2 expression and promotes the gain of stemness in astrocytes in ischemic stroke mice
Luo, X., Zhu, Z., Zheng, T., Li, D., Wei, Y., Yang, H., Yu, H., Han, J., Wang, Y., Wang, L., et al. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07806-7 · Cited by 13 · see citing works
Out of the core: the impact of focal ischemia in regions beyond the penumbra
Koukalova, L., Chmelová, M., Amlerova, Z., & Vargová, L. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1336886 · Cited by 13 · see citing works
Identification of potential biomarkers of cuproptosis in cerebral ischemia
Qin, L., Cao, X., Huang, T., Liu, Y., & Li, S. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1410431 · Cited by 13 · see citing works
“However, the soaring incidence of IS among postmenopausal women (12), with enlarged infarction and aggravated brain damage in ovariectomized rats (13), poses a critical threat.”
Social influences on microglial reactivity and neuronal damage after cardiac arrest/cardiopulmonary resuscitation
Gaudier‐Diaz, M. M., Haines, A. H., Zhang, N., & DeVries, A. C. (2018) · Physiology & Behavior · doi:10.1016/j.physbeh.2018.06.012 · Cited by 13 · see citing works
Fecal microbiota transplantation unveils sex-specific differences in a controlled cortical impact injury mouse model
Pasam, T., & Dandekar, M. P. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1336537 · Cited by 12 · see citing works
Genetic Modulators of Traumatic Brain Injury in Animal Models and the Impact of Sex-Dependent Effects
Inampudi, C., Ciccotosto, G. D., Cappai, R., & Crack, P. J. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2019.6955 · Cited by 12 · see citing works
“34 In a disease context, sex difference is known to inﬂuence the extent and severity of neurological diseases such as stroke, 35,36 post-traumatic stress disorder, 37,38 schizophrenia, 39,40 Parkinson’s disease, 41,42 and Alzheimer’s disease.”
Sex influence in ischemic stroke severity and outcome among metabolically unhealthy overweight patients
Viticchi, G., Falsetti, L., Plutino, A., Bartolini, M., Buratti, L., & Silvestrini, M. (2020) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2020.116955 · Cited by 12 · see citing works
CCL2 (C-C Motif Chemokine Ligand 2) Biomarker Responses in Central Versus Peripheral Compartments After Focal Cerebral Ischemia
Shi, J., Li, W., Zhang, F., Park, J. H., An, H., Guo, S., Duan, Y., Wu, D., Hayakawa, K., Lo, E. H., et al. (2021) · Stroke · doi:10.1161/strokeaha.120.032782 · Cited by 12 · see citing works
Shifts in the spatiotemporal profile of inflammatory phenotypes of innate immune cells in the rat brain following acute intoxication with the organophosphate diisopropylfluorophosphate
Andrew, P. M., MacMahon, J. A., Bernardino, P. N., Tsai, Y., Hobson, B. A., Porter, V. A., Huddleston, S. L., Luo, A., Bruun, D. A., Saito, N. H., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03272-8 · Cited by 11 · see citing works
“Across disease states, sex is known to modify immune function [104–106], and it is possible that there are innate sex differences in the extremes of pro-and anti-inflammatory glial polarization following acute OP intoxication.”
Background
Single-cell RNA sequencing reveals functional heterogeneity and sex differences of glioma-associated brain macrophagesPreprint
Ochocka, N., Segit, P., Walentynowicz, K. A., Wojnicki, K., Cyranowski, S., Swatler, J., Mieczkowski, J., & Kaminska, B. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/752949 · Cited by 11 · see citing works
Systemic Candesartan Treatment Modulates Behavior, Synaptic Protein Levels, and Neuroinflammation in Female Mice That Express Human APOE4
Scheinman, S. B., Zaldua, S., Dada, A., Krochmaliuk, K., Dye, K., Marottoli, F. M., Thatcher, G. R. J., & Tai, L. M. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.628403 · Cited by 11 · see citing works
Neuroprotection or Sex Bias: A Protective Response to Traumatic Brain Injury in the Females
Yatoo, M. I., Bahader, G. A., Beigh, S. A., Khan, A. M., James, A. W., Asmi, M. R., & Shah, Z. A. (2023) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527323666230817102125 · Cited by 9 · see citing works
Human monocyte subtype expression of neuroinflammation- and regeneration-related genes is linked to age and sex
Tampé, J., Monni, E., Palma-Tortosa, S., Brogårdh, E., Böiers, C., Lindgren, A. G., & Kokaia, Z. (2024) · PLoS ONE · doi:10.1371/journal.pone.0300946 · Cited by 9 · see citing works
Role of hyperhomocysteine, thyroid dysfunction and their interaction in ischemic stroke patients with non-valvular atrial fibrillation
Wang, L., & Zhang, Y. (2020) · Scientific Reports · doi:10.1038/s41598-020-69449-2 · Cited by 9 · see citing works
Floral development in the androdioecious tree Tapiscia sinensis: Implications for the evolution to androdioecy
Xin, G., Jia, G., Ren, X., Wang, Y., Zhao, P., & Liu, W. (2019) · Journal of Systematics and Evolution · doi:10.1111/jse.12517 · Cited by 9 · see citing works
Using iPSC Models to Understand the Role of Estrogen in Neuron–Glia Interactions in Schizophrenia and Bipolar Disorder
de Assis, D. R., Szabó, A., Osete, J. R., Puppo, F., O’Connell, K. S., Akkouh, I. A., Hughes, T., Frei, E., Andreassen, O. A., & Djurovic, S. (2021) · Cells · doi:10.3390/cells10020209 · Cited by 10 · see citing works
Immunonutrition: future perspective in neurodegenerative disorders
Claro, C., Rivero‐Pino, F., Torrecillas-López, M., Jiménez-González, V., & la Paz, S. M. (2024) · Nutritional Neuroscience · doi:10.1080/1028415x.2024.2425565 · Cited by 8 · see citing works
“It has been demonstrated that several neuroinflammation parameters (including cell death programs, cell – cell signaling pathways, and systemic and organ-specific immune responses) are highly influenced by sex differences, genetic and epigenetic factors [49].”
Proinflammatory Risk Factors in Patients with Ischemic Stroke: A Systematic Review and Meta-Analysis
Gerdanovics, A., Stănescu, I., Mîrza, C.-M., Dogaru, G. B., Nicula, C. A., Boarescu, P.-M., Gerdanovics, C.-A., & Bulboacă, A. E. (2025) · Antioxidants · doi:10.3390/antiox14101229 · Cited by 8 · see citing works
Effects of acrobatic training on spatial memory and astrocytic scar in CA1 subfield of hippocampus after chronic cerebral hypoperfusion in male and female rats
Martini, A. P. R., Hoeper, E., Pedroso, T. A., Carvalho, A. V. S., Odorcyk, F. K., Fabres, R. B., Pereira, N. D. S. C., & Netto, C. A. (2022) · Behavioural Brain Research · doi:10.1016/j.bbr.2022.113935 · Cited by 8 · see citing works
Brain Endothelial Cells Activate Neuroinflammatory Pathways in Response to Early Cerebral Small Vessel Disease (CSVD) Patients’ Plasma
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Susceptibility of PON1/PON2 Genetic Variations to Ischemic Stroke Risk in a Chinese Han Population
Pan, Y., He, B., Sun, H., Xu, T., Pan, B., Wang, S., & Mei, Y. (2020) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s275341 · Cited by 7 · see citing works
EPO regulates neuronal differentiation of adult human neural-crest derived stem cells in a sex-specific manner
Niemann, T., Greiner, J. F. W., Kaltschmidt, C., & Kaltschmidt, B. (2023) · BMC Neuroscience · doi:10.1186/s12868-023-00789-1 · Cited by 7 · see citing works
Crosstalk between the aging intestinal microflora and the brain in ischemic stroke
Pluta, R. M., Jabłoński, M., Januszewski, S., & Czuczwar, S. J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.998049 · Cited by 7 · see citing works
“A damaged core initiates inflammation and apoptosis through glutamate excitotoxicity, changes in calcium levels and oxidative stress (Spychala et al., 2017).”
Background
Influence of sex, age and diabetes on brain transcriptome and proteome modifications following cerebral ischemia
Ramiro, L., Faura, J., Simats, A., García‐Rodríguez, P., Ma, F., Martín, L., Canals, F., Rosell, A., & Montaner, J. (2023) · BMC Neuroscience · doi:10.1186/s12868-023-00775-7 · Cited by 7 · see citing works
Withdrawn: Ischemic stroke across sexes: What is the status quo?
Liberale, L., Carbone, F., Montecucco, F., Gebhard, C., Lüscher, T. F., Wegener, S., & Camici, G. G. (2018) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2018.04.001 · Cited by 7 · see citing works
Sex-specific association of weight-adjusted waist index with mortality in stroke survivors: A national longitudinal cohort study
Liu, F., Chen, J., Yao, Y., Ren, R., Yu, Y., & Hu, Y. (2024) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2024.09.013 · Cited by 6 · see citing works
Protein profiling identified mitochondrial dysfunction and synaptic abnormalities after dexamethasone intervention in rats with traumatic brain injury
Liu, B., Zhang, B., Feng, J., Mao, X., Xu, X., Dong, J., & Liu, B.-Y. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.313047 · Cited by 6 · see citing works
“Animals Sex has a profound effects on the outcome of ischemic or traumatic brain injury, which could be due to the differences of sex steroid hormones between males and females (Roof and Hall, 2000; Spychala et al., 2017).”
Background
Sex modulated effects of sarin exposure in rats: Toxicity, hypothermia and inflammatory markers
Pittel, Z., Grauer, E., Gez, R., Shlomovich, Y., Baranes, S., & Chapman, S. (2018) · NeuroToxicology · doi:10.1016/j.neuro.2018.04.002 · Cited by 6 · see citing works
Effect of Cannabinoid 2 Receptor Modulation on the Peripheral Immune Response in Central Nervous System Injury-Induced Immunodeficiency Syndrome
Sultana, S., Burkovskiy, I., Zhou, J., Kelly, M., & Lehmann, C. (2021) · Cannabis and Cannabinoid Research · doi:10.1089/can.2020.0130 · Cited by 6 · see citing works
“44 There are also other lines of evidence suggesting variations between sex in microglia, dendritic cells, and neutrophils, potentially drawing more differences in sex-associated pathophysiological consequences of CNS injury.”
Genetic inhibition of PKCε attenuates neurodegeneration after global cerebral ischemia in male mice
Kumar, V., Weng, Y., Wu, Y., Huang, Y., Liu, T., Kristián, T., Liu, Y., Tsou, H., & Chou, W. (2018) · Journal of Neuroscience Research · doi:10.1002/jnr.24362 · Cited by 5 · see citing works
A Pilot Systematic Review and Meta-analysis of Neuroprotective Studies in Female Rodent Models of Ischemic Stroke
Gunderson, M. L., Heer, S., & Klahr, A. C. (2023) · Translational Stroke Research · doi:10.1007/s12975-023-01134-8 · Cited by 5 · see citing works
Age-Dependent Microglial Response to Systemic Infection
Cyr, B. S., & Vaccari, J. P. D. R. (2021) · Cells · doi:10.3390/cells10051037 · Cited by 5 · see citing works
“There is also evidence that sex-specific differences exist in the immune response and cell signaling [34].”
Background
Impact of Sex on Clinical Outcomes of Tandem Occlusion in Acute Ischemic Stroke Patients Treated With Mechanical Thrombectomy. A Propensity‐Matched Analysis
D’Anna, L., Foschi, M., Valente, M., Zhang, L., Sacco, S., Ornello, R., Mansoor, N. M., Fallon, M., Jaramillo, A. G., Sponza, M., et al. (2025) · European Journal of Neurology · doi:10.1111/ene.70044 · Cited by 4 · see citing works
Precision Medicine in Acute Brain Injury: A Narrative Review
Mahajan, C., Kapoor, I., & Prabhakar, H. (2020) · Journal of Neurosurgical Anesthesiology · doi:10.1097/ana.0000000000000710 · Cited by 4 · see citing works
High Levels of Thromboxane (TX) Are Associated with the Sex-Dependent Non-Dipping Phenomenon in Ischemic Stroke Patients
Drozd, A., Szczuko, M., Bohatyrewicz, A., Jurewicz, A., & Kotlęga, D. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11092652 · Cited by 4 · see citing works
“Of course, other pro-inflammatory factors may also be involved in the occurrence of this singularity, supporting the thesis of other researchers on the role of gender in the pathogenesis of stroke, including the presence of inflammation [48].”
Result

Authors: Spychala, M. S., Honarpisheh, P., & McCullough, L. D.
Affiliations: The University of Texas Health Science Center at Houston (US)
Corresponding author: McCullough, Louise D.
ORCID: Honarpisheh, Pedram
McCullough, Louise D.
Venue: Journal of Neuroscience Research
Publisher: Wiley
Published: 2016-11-07
Volume: 95
Issue: 1-2
Pages: 462-471
ISSN: 0360-4012 (ISSN-L)
1097-4547
DOI: 10.1002/jnr.23962
PMC: PMC5217708
OpenAlex: W2553184470
Cited by: 127
References: 83
Citations by year: 2026: 6 · 2025: 7 · 2024: 14 · 2023: 9 · 2022: 19 · 2021: 21 · 2020: 16 · 2019: 16 · 2018: 17 · 2017: 2
FWCI: 1.58
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Journal of Neuroscience Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: NIH (RO1NS055215, R21NS090422)
Topics: Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
Keywords: sex differences, ischemic stroke, neuroinflammation, neuroprotection, stroke risk factors, postmenopausal women, stroke prevention, acute stroke care, stroke recovery, epigenetics, cell death, systemic immune response, stroke in women
MeSH terms: Neuroprotection, Brain Ischemia, Encephalitis, Humans, Sex Characteristics, Stroke

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Sex differences in neuroinflammation and neuroprotection in ischemic stroke

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