Blockade of adrenoreceptors inhibits the splenic response to stroke

Abstract

Recent studies have highlighted the involvement of the peripheral immune system in delayed cellular degeneration after stroke. In the permanent middle cerebral artery occlusion (MCAO) model of stroke, the spleen decreases in size. This reduction occurs through the release of splenic immune cells. Systemic treatment with human umbilical cord blood cells (HUCBC) 24 hours post-stroke blocks the reduction in spleen size while significantly reducing infarct volume. Splenectomy two weeks prior to MCAO also reduces infarct volume, further demonstrating the detrimental role of this organ in stroke-induced neurodegeneration. Activation of the sympathetic nervous system after MCAO results in elevated catecholamine levels both at the level of the spleen, through direct splenic innervation, and throughout the systemic circulation upon release from the adrenal medulla. These catecholamines bind to splenic α and β adrenoreceptors. This study examines whether catecholamines regulate the splenic response to stroke. Male Sprague-Dawley rats either underwent splenic denervation two weeks prior to MCAO or received injections of carvedilol, a pan adrenergic receptor blocker, prazosin, an α1 receptor blocker, or propranolol, a β receptor blocker. Denervation was confirmed by reduced splenic expression of tyrosine hydroxylase. Denervation prior to MCAO did not alter infarct volume or spleen size. Propranolol treatment also had no effects on these outcomes. Treatment with either prazosin or carvedilol prevented the reduction in spleen size, yet only carvedilol significantly reduced infarct volume (p<0.05). These results demonstrate that circulating blood borne catecholamines regulate the splenic response to stroke through the activation of both α and β adrenergic receptors.

Intravenous multipotent adult progenitor cell therapy for traumatic brain injury: Preserving the blood brain barrier via an interaction with splenocytes

“…Separate experiments completed by Offner et al have shown a peripheral increase in production of the pro inflammatory cytokines TNF , IFN , IL-6, MCP-1, and IL-2 after ischemic stroke . Further work completed by Ajmo et al has shown that ischemic stroke is associated with adrenergic output that stimulates the spleen to release immune (T and B cells) into the systemic circulation that ultimately lead to increased cavity size after MCAO stroke in a rodent model (Ajmo, et al, 2009). Furthermore, Verdrame et al have shown similar results indicating the release of immune cells (CD8+ T cells) is correlated with a reduction in splenic mass.…”

Inflammatory mechanisms involved in brain injury following cardiac arrest and cardiopulmonary resuscitation

“…By these molecules, infiltrating neutrophils amplify a cerebral inflammatory response that may exacerbate post-ischemic brain damage (49,51,52). Furthermore, infiltrating neutrophils are the primary source of enhanced matrix metalloproteinase 9 activity in the ischemic brain, which is a critical mechanism underlying the breakdown of the BBB and the exacerbation of neurological injury (53).…”

Acute splenic responses in patients with ischemic stroke and intracerebral hemorrhage

“…14 It has further been demonstrated in experimental stroke models that pre or immediate poststroke surgical removal or irradiation of the spleen attenuates these responses, and results in reduced stroke lesion size and enhanced recovery. 5,[14][15][16][17][18][19] The pre-clinical body of evidence raises an exciting possibility that novel therapies can be designed to target the spleen as an approach to modulate post-stroke inflammation and dampen secondary brain injury. [20][21][22][23][24] However, the road to translation of these findings in the clinical setting is beset with challenges.…”