Background/Objectives: Sepsis has been shown to depress arterial baroreceptor function, and this effect is counterbalanced by the cholinergic anti-inflammatory pathway. Considering the importance of central adenosine receptors in baroreceptor function, this study tested whether central adenosine A3 receptors (A3ARs) modulate the cholinergic-baroreflex interaction in sepsis and whether this interaction is modulated by mitogen-activated protein kinases (MAPKs) and related proinflammatory cytokines. Methods: Sepsis was induced by cecal ligation and puncture (CLP) and rats were instrumented with femoral and intracisternal (i.c.) catheters. Baroreflex sensitivity (BRS) was measured 24 h later in conscious animals using the vasoactive method, which correlates changes in blood pressure caused by i.v. phenylephrine (PE) and sodium nitroprusside (SNP) to concomitant reciprocal changes in heart rate. Results: The reduction in reflex bradycardic (BRS-PE), but not tachycardic (BRS-SNP), responses elicited by CLP was reversed by i.v. nicotine in a dose-related manner. The BRS-PE effect of nicotine was blunted following intracisternal administration of IB-MECA (A3AR agonist, 4 µg/rat). The depressant action of IB-MECA on the BRS facilitatory action of nicotine was abrogated following central inhibition of MAPK-JNK (SP 600125), PI3K (wortmannin), and TNFα (infliximab), but not MAPK-ERK (PD 98059). Additionally, the nicotine suppression of sepsis-induced upregulation of NFκB and NOX2 expression in the nucleus tractus solitarius (NTS) was negated by A3AR activation. The molecular effect of IB-MECA on NFκB expression disappeared in the presence of SP 600125, wortmannin, or infliximab. Conclusions: The central PI3K/MAPK-JNK/TNFα pathway contributes to the restraining action of A3ARs on cholinergic amelioration of sepsis-induced central neuroinflammatory responses and impairment of the baroreceptor-mediated negative chronotropism.

Background/Objectives: Sepsis remains one of the most serious and possibly fatal complications encountered in intensive care units. Considering the frequent use of narcotic analgesics in this setting, we investigated whether the cardiovascular and peripheral and central inflammatory features of sepsis could be modified by morphine. Methods: Rats were instrumented with femoral and intracisternal (i.c.) indwelling catheters and sepsis was induced by cecal ligation and puncture (CLP). Results: The i.v. administration of morphine (3 and 10 mg/kg) significantly and dose-dependently aggravated septic manifestations of hypotension and impaired cardiac autonomic activity, as reflected by the reductions in indices of heart rate variability (HRV). Cardiac contractility (dP/dtmax) was also reduced by morphine in septic rats. The morphine effects were mostly eliminated following (i) blockade of μ-opioid receptors by i.v. naloxone and (ii) inhibition of central PI3K, MAPK-ERK, MAPK-JNK, NADPH oxidase (NADPHox), or Rho-kinase (ROCK) by i.c. wortmannin, PD98059, SP600125, diphenyleneiodonium, and fasudil, respectively. Further, these pharmacologic interventions significantly reduced the heightened protein expression of toll-like receptor 4 (TLR4) and monocyte chemoattractant protein-1 (MCP1) in brainstem rostral ventrolateral medullary (RVLM), but not cardiac, tissues of CLP/morphine-treated rats. Conclusions: Morphine worsens cardiovascular and autonomic disturbances caused by sepsis through a mechanism mediated via μ-opioid receptors and upregulated central inflammatory, chemotactic, and oxidative signals. Clinical studies are warranted to re-affirm the adverse cardiovascular interaction between opioids and the septic challenge.

Organophosphate pesticides (OPPs) are widely used in agriculture and are associated with metabolic dysregulation and cognitive impairment. Emerging evidence links OPP exposure to insulin resistance and diabetes mellitus, a condition known to negatively impact brain function. Prior investigations in our laboratory identified significant dysregulation of arachidonic acid (AA) metabolites associated with the endocannabinoid system in both diabetic patients and those with chronic OPP exposure, with a marked reduction in serum AA levels in the OPP-exposed cohort. This study investigates the impact of OPP exposure and pre-diabetes on the hippocampal proteome and whether AA supplementation can mitigate the resulting neuronal proteomic alterations. Using a controlled rat model, high-resolution LC-MS/MS-based proteomics identified differentially expressed proteins across experimental groups. Both OPP exposure and pre-diabetes were associated with increased cognitive impairment and were associated with overlapping disruptions in pathways related to insulin resistance, mitochondrial function, synaptic plasticity, and neuronal development. AA supplementation mitigated cognitive decline and stabilized synaptic and metabolic proteins; however, residual pathway dysregulation highlights the complexity of these stressors. Our results reveal novel molecular intersections between environmental and metabolic drivers of cognitive impairment, establishing a rationale for further research into inexpensive, protective dietary interventions.

Acetylcholine (ACh) and adenosine triphosphate (ATP) are the major neurotransmitters in bladder contraction. This study investigates the modulatory role of some prostanoids in cholinergic and purinergic pathways in normal and cystitis. Cystitis was induced in rats by cyclophosphamide single injection (300 mg/kg) and confirmed histopathologically. Organ bath experiments were implemented using isolated detrusor muscles. Bladder contraction was induced by electrical stimulation and by ACh or ATP direct addition. Cystitis attenuated bladder contractility. Alprostadil and selexipag amplified neurogenic and cholinergic contractions in normal and inflamed bladder. The neurogenic contractions amplification was higher in cystitis with 54.63 ± 42.11% compared to 18.77 ± 5.98% in normal at 10 ⁻⁷ M selexipag. While cholinergic contraction amplification was higher in cystitis using selexipag and alprostadil, the amplifying effect of 10 ⁻⁶ M alprostadil was 21.07 ± 15.07% and 128.02 ± 76.61% and the amplifying effect of 10 ⁻⁶ M selexipag was 39.51 ± 19.72% and 227.6 ± 229.59% in normal and cystitis respectively. At higher concentrations, selexipag and alprostadil amplified purinergic contractions in normal bladder. RO1138452 inhibited neurogenic and cholinergic contractions in normal and inflamed bladder, with less inhibition of cholinergic contractions in inflamed bladder with 26.6 ± 20.72% compared to 54.22 ± 19.6% in normal. The same was observed using SC51322 but cholinergic contraction inhibition was not significant in normal. Both antagonists inhibited purinergic contractions in normal. S18886 inhibited purinergic contractions in normal bladder. EP ₁ and IP receptors may play a role in bladder contraction. TP receptor is involved in purinergic signaling in normal physiology. Selexipag and alprostadil may have a potential beneficial action in cystitis and merit further investigation.