The Effect of a New N-hetero Cycle Derivative on Behavior and Inflammation against the Background of Ischemic Stroke

Abstract

Ischemic stroke triggers a whole cascade of pathological changes in the brain, one of which is postischemic inflammation. Since in such cases thrombolytic therapy is often not possible, methods that modulate inflammation and affect microglia become particularly interesting. We synthesized 3-(2-oxo-4-phenylpyrrolidin-1-yl)propane-1-sulfonate calcium(II) (Compound 4) and studied its anti-inflammatory activity in in vitro and in vivo models of inflammation and ischemia. Macrophage cell line RAW 264.7 was treated with lipopolysaccharides (LPS) and Compound 4 at various dosages to study the cytokine profile using real-time PCR and cytometric bead array (CBA). Stroke in rats was simulated by the middle cerebral artery occlusion method (MCAO). Several tests were performed to characterize the neurological deficit and locomotor activity of the rats, and afterwards, postmortem, the number of astrocytes was counted using immunohistochemistry. Compound 4 in in vitro tests dose-dependently reduced the expression of interleukin-1β (IL1β), and inducible nitric oxide synthase (iNOS) genes in cell culture and increased the concentration of cytokines: interleukin-2, 4, 6 (IL-2, IL-4, and IL-6). In vivo Compound 4 increased the orienting-exploratory behavior, and reduced neurological and motor deficit. The number of astrocytes that promote and support inflammation was lower in the group treated with Compound 4. The stroke volume measured by magnetic resonance imaging (MRI) showed no difference. We have shown that Compound 4 demonstrates anti-inflammatory activity by increasing the synthesis of anti-inflammatory and reducing pro-inflammatory cytokines, and positively affects the neurological deficit in rats. Thus, Compound 4 has a high therapeutic potential in the management of patients after a stroke and requires further study of its neuroprotective properties.

Pyridine Carboxamides Based on Sulfobetaines: Design, Reactivity, and Biological Activity

“…Previously, we managed to increase the bioavailability of Phenotropil by introducing chemical modification, which led to the production of a water-soluble form based on taurine [ 1 ]. The same approach was shown for homotaurine [ 3 ].…”

“…For many years, our group has focused on discovering and developing new heterocyclic compounds that have nootropic, anti-inflammatory, and antidepressant activities. Our main goal is to develop effective medications for treating cognitive impairments, including ischemic stroke and its complications [ 1 , 2 , 3 , 4 ]. The recent COVID-19 pandemic highlighted the emerging need for these kinds of therapeutic agents.…”

TMAO Promotes NLRP3 Inflammasome Activation of Microglia Aggravating Neurological Injury in Ischemic Stroke Through FTO/IGF2BP2

“…It has been reported that microglia promoted the release of inflammatory cytokines in stroke. 8 In addition, NLRP3 inflammasome is activated in microglia under the context of stroke. 9 NLRP3 is an inflammasome that impairs cellular function, and the association of NLRP3 with many diseases has been extensively studied, consisting of traumatic brain injury (TBI) and myocardial ischemia/reperfusion (I/R) injury.…”