Table 3.

Treatments of stroke with spleen as target.

Treatment		Target Cells or Moleculars	Effects on the Spleen		Effects on the Injured Brain		Refs.
Splenectomy		All the splenocytes	-		• Reduced infarct volume and edema, improved neurobehavioral and infarct outcomes. A reduction in peripheral immune cell infiltration into the brain and decreased levels of peripheral inflammatory cytokines after stroke. • It could not promote long-term functional recovery after MCAO.		[19, 24, 26, 27, 28, 29,30, 69, 71, 72]
Stem cells therapy		Spleen cells	Prior to migrating to the spleen. Rescued the spleen weight, splenic CD8+T-cells. Attenuated splenic activations of TNF-α, IL-6, NF-κB		• Decrease the infarct volume and have significant recovery in behavioral performance. • Reduced the brain oedema and the initial neurologic deficits, infalmmatory infiltrations and apoptosis.		[4, 68, 69, 81, 82, 83, 85, 86, 88, 89]
LPS-Preconditioning		Ly6Chigh monocytes from the spleen	Mobilized a Ly6Chigh monocytes from the spleen to brain and meninges after stroke.		Reduced infarct volume. Increased Ly6Chigh monocytes in brain and meninges, where they suppressed postischemic inflammation and neutrophil influx into the brain parenchyma after stroke.		[46]
remote ischemic preconditioning (RIPC)		Lymphocytes in spleen	Increased splenic volume with an expansion of splenic lymphocytes 3 days after MCAO. promptly increased the percentages of CD3+CD8+cytotoxic T (Tc) cells in the spleen with a relatively delayed elevation in CD3+CD161+ natural killer T (NKT) and CD3-CD45RA+ B lymphocytes.		Reduced infarct volume and neurological deficit and reduced brain infiltration of Tc and NKT cells.		[93]
remote ischemic limb conditioning (RLC)		CCR2+ monocyte subset in spleen	Adoptive transfer of CCR2-deficient monocytes abolished RLC-mediated protection in splenectomized mice. Shifted circulating monocytes to a CCR2+ pro-inflammatory monocyte subset		Reduced acute brain injury, swelling, and improved motor/gait function in chronic stroke.		[94]
carvedilol		Pan adrenergic receptors in the spleen	Prevented the reduction in spleen size.		Significantly reduced infarct volume		[5] [34]
prazosin		α1 receptor in the spleen	Prevented the reduction in spleen size		No effect
propranolol		β receptor in the spleen	No effect or Partly reverse the immunodepression and the reduction in spleen volume		No effect
Simvastatin		Mitochondria of splenocytes	Reduced stroke-induced spleen atrophy and splenic apoptosis via increased mitochrondrial antiapoptotic Bcl-2 expression and decreased proapoptotic Bax translocation from cytosol into mitochondria.		Inhibited brain interferon-γ (3 days) and reduced infarct volume and neurological deficits (5 days) after stroke.		[19]
Treatment	Target Cells or Moleculars			Effects on the Spleen		Effects on the Injured Brain		Refs.
αCD147(an antiCD147 antibody)	monocytes/macrophages in spleen			Reduced the early splenic inflammatory response. Reduced the early proinflammatory activation of splenic monocytes/macrophages after tMCAO		• Reduced Ly6Chi monocyte/macrophages in the brain. • CD147 as a key mediator of the spleen’s inflammatory activation in response to cerebral ischemia.		[95]
Recombinant mouse IL-33	splenic T cells			Reduced INF-γ+ Tcells and incteased Foxp3+ T cells in the spleen tissue. Deceased the production of INF-γ and increased the secretion of IL-4, IL-10, and TGF-β from at 24 h after MCAO.		Attenuated neurological deficit scores and infarct volumes after MCAO.		[97]
RTL551 RTL1000	Spleinc T cells			Mitigated splenic atrophy. Significantly Increased the splenic cells in the spleen after MCAO. Reduced expression of the chemokine receptors, CCR5 in the spleen.		• Reduced cortical and total stroke lesion size by approximately 50%, inhibited the accumulation of inflammatory cells, particularly macrophages/activated microglial cells and dendritic cells. • Reduced the frequency of the activation marker, CD44, on T-cells in the blood and in the ischemic hemisphere.		[53, 99, 100, 101]
selective endovascular cooling	Splenic cells			Promotes anti-inflammatory IL-10 elevation in the spleen. Hypothermia-exposed splenocytes co-cultured with primary rat neurons upregulate BNDF and IL-10 and improve cell viability following OGD.		Increase BDNF expression in the motor cortex, striatum, and hippocampal CA3.		[102]
Clodronate liposomes	Macrophages in spleen			Depleted 80% of the macrophages in the spleen		Reduced macrophage infiltration in the brain. Enhanced the microvessel density in the peri-infarct region, decreased brain atrophy, and promoted neurological recovery.		[52]