Table 1.

Pre-clinical studies examining sex-specific responses in ischemic stroke.

Study	Species and Strain	Age	Key Findings
Villapol et al.85	C57BL6/J Mice	Post-natal day 9 (P9)	Neonatal ischemia models showed that female mice had significantly smaller infarcts compared to males as far as 3 months post-ischemia. Increased activation of microglia/macrophages and higher myeloid-specific brain infiltrates were observed in males.
Borgus et al.86	Sprague-Dawley Rats	Not reported	Sex and region-specific differences in adenosine, a ubiquitous neuromodulator, were seen.
Ahnstedt et al.87	C57BL/6N Mice	20-22 months	Independent of ischemic damage, aged males had significantly increased peripheral immune responses in the gut and exacerbated neuroinflammation in the sub-acute phase of stroke.
Dotson et al.88	C57BL/6J or PPARα knockout (KO) Mice (C57BL/6J background)	2-4 months	PPARα, a nuclear receptor transcription factor, plays a key role in perpetuating sex-specific peripheral immune responses following ischemic stroke.
Ahnstedt et al.89	C57BL/6J Mice	Young (3-4 months) and middle-aged (15 - 16 months)	Female mice had elevated levels of pro-inflammatory T cells and suppressed levels of anti-inflammatory Tregs in adipose tissue. The degree of adiposity, a major risk for ischemic stroke, may be phenotypically distinct across sexes.
Manwani et al.90	C57BL/6 Mice	Young (5-6 months), middle aged (14-15 months), and aged (20-22 months)	Heterogenic age- and sex-specific changes were evident in the post-stroke inflammatory milieu. Higher inflammatory macrophages and less lymphocytic infiltration in cycling females. Exacerbated splenic contraction in aged females. Age-specific increases in pro-inflammatory T cells, DCs, and microglia in the brain.
Davis et al.91	Sprague-Dawley Rats	18 months	Sex-specific effects of leukemia inhibitory factor treatment in mice seen following ischemic stroke. Sex differences in peripheral splenic responses and production of pro-inflammatory cytokine including IL-3 in females.
Jackson et al.92	Wister Rats	2-3 months	Sex differences in diabetes, a major risk factor for ischemic stroke. Higher pro-inflammatory TH17 in female brains after stroke. Expansion of T cell subsets was sex-dependent and regulated by the sexual dimorphic effects of diabetes.
McCullough et al.93	C57BL/6J XYM and wild-type C57BL/6J Mice	18-20 months	X chromosome compliment (XX) regulates ischemic damage in aged animals (worse in females). Sex-specific effects of innate immune responses following ischemic stroke.
Mirza et al.94	C57BL/6 Mice	Post-natal day 10 (P10)	Sex-based innate immune response differed with increase microglial activation and infiltration of peripheral leukocytes following HIE in males.
Xiong et al.95	BALB/cJ and IL-4 KO (BALB/c-IL-4tm2Nnt/J) Mice	2-3 months	Neuroprotective mechanisms after stroke in female mice are mediated by IL-4. Females exhibit activation of anti-inflammatory M2 microglia as well as reduced in infiltration of peripheral leukocytes.
Nguyen et al.96	C57BL/6 and BALB/c Mice	Young (3-4 months) and aged (18 months)	Sex-based differences in cytokines and chemokines within the infarct area at the liquefactive stage of necrosis after stroke.
Dotson et al.97	C57BL/6J Mice	Not reported	Splenectomy prior to experimental stroke abolished sex differences in infarct volume and stroke-induced monocyte and microglia activation.
Wang et al.98	C57BL/6J Mice	2-3 months	Adoptive transfer of peripheral immune cells (CD4/ CD8/ CD11b), prior to stroke had no effects on post-stroke inflammation. Suggested that other immunoregulatory factors exert sex-based effects of the spleen on post-stroke outcomes.
Raval et al.99	Sprague-Dawley Rats	Young (6-7 months) and retried breeder (9-13 months)	Sex differences in the inflammasome related to the reproductive hormones may contribute to sex-based differences in regulation of inflammatory states, seen in microglia activation and immune cell infiltration in the brain post-stroke.
Liu et al.100	CaMKK β knockout (KO) and CaMK IV KO Mice (C57BL/6J background)	3-4 months	Pharmacological inhibition of CaMMK downstream signaling exacerbated stroke outcomes as characterized by BBB impairment and activation of pro-inflammatory responses seen only in females following stroke.
Li et al.101	Fischer Rats	2 months	Female rats exhibited a significantly higher inflammatory response following stroke in infarcts across all severities. However, severe infarcts within the cerebral regions in males were significantly larger compared to female counterparts.