Beyond the Brain: The Systemic Pathophysiological Response to Acute Ischemic Stroke

Abstract

Stroke research has traditionally focused on the cerebral processes following ischemic brain injury, where oxygen and glucose deprivation incite prolonged activation of excitatory neurotransmitter receptors, intracellular calcium accumulation, inflammation, reactive oxygen species proliferation, and ultimately neuronal death. A recent growing body of evidence, however, points to far-reaching pathophysiological consequences of acute ischemic stroke. Shortly after stroke onset, peripheral immunodepression in conjunction with hyperstimulation of autonomic and neuroendocrine pathways and motor pathway impairment result in dysfunction of the respiratory, urinary, cardiovascular, gastrointestinal, musculoskeletal, and endocrine systems. These end organ abnormalities play a major role in the morbidity and mortality of acute ischemic stroke. Using a pathophysiology-based approach, this current review discusses the pathophysiological mechanisms following ischemic brain insult that result in end organ dysfunction. By characterizing stroke as a systemic disease, future research must consider bidirectional interactions between the brain and peripheral organs to inform treatment paradigms and develop effective, comprehensive therapeutics for acute ischemic stroke.

Linalool protects hippocampal CA1 neurons and improves functional outcomes following experimental ischemia/reperfusion in rats

“…Stroke, a predominant cause of mortality and physical impairment, has a shortage of curative therapies [30]. In this particular study, we used a global cerebral I/R injury experimental model that can simulate the human clinical stroke due to cardiac arrest or carotid artery occlusion.…”

Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders

“…Binding of damage-associated molecular patterns and pathogen-associated molecular patterns, molecular motifs localized on pathogens, to TLRs and their conformational alterations stimulate a cascade of downstream signaling and trigger inflammatory responses [ 48 ]. TLR signaling is generally divided into two main downstream adaptor proteins; the myeloid differentiation primary response 88 (MyD88)-dependent and adapter-inducing interferon-β (TRIF)-dependent pathways [ 49 ]. The canonical adaptor molecule MyD88 activates NF-κB through nearly all TLRs, except TLR3 [ 50 ].…”

Therapeutic efficacy of α7 ligands after acute ischaemic stroke is linked to conductive states of α7 nicotinic ACh receptors

“…These results are significant because they define ionotropic efficacy of α7 nAChRs as a critical determinant of the therapeutic potential of α7 agents in stroke. The impact of α7 "metagonists" and partial agonists on the time course of central and peripheral immune responses after acute ischaemic stroke that result in secondary injury is not explored in this study and deserves a thorough investigation because α7 nAChRs are directly involved in modulation of both immunoreactivity and immunosuppression after acute ischaemic stroke (Balch et al, 2020;Brambilla et al, 2013). Thus, these endogenous mechanisms (Haeusler et al, 2008;Meisel et al, 2005;Prass et al, 2003) are expected to be affected by cholinergic agents such as 4OH-GTS-21 and NS6740.…”