Central thromboxane A2, prostaglandin F2α, prostaglandin E, and prostaglandin D contribute to the cardiovascular effects elicited by nesfatin-1.

Background/aim: Our recent study revealed that the expression of lipoxygenase (LOX) and cyclooxygenase (COX) enzymes in the hypothalamus is activated by nesfatin-1, leading to the liberation of leukotrienes and prostaglandins (PG), respectively. Moreover, our prior report explained that intracerebroventricular (ICV) nesfatin-1 treatment triggers cardiovascular responses mediated by central LOX and COX enzymes. Building upon our prior reports, the present investigation sought to clarify the role of cardiovascularly active central COX products, such as thromboxane (TX) A2, PGF2α, PGE, and PGD, in orchestrating nesfatin-1-evoked reactions in mean arterial pressure (MAP) and heart rate (HR). Materials and methods: The Sprague Dawley rats, which had guide cannula in the lateral ventricle for intracerebroventricular (ICV) injections and catheter in arteria femoralis for monitoring MAP and HR, were underwent central pretreatment with furegrelate (the TXA2 synthase inhibitor), PGF2α-dimethylamine (PGF2α-DA, the PGF2α receptor antagonist), or AH6809 (the PGE and PGD receptor antagonist), 5 min prior to ICV nesfatin-1 administration. The cardiovascular parameters were observed and recorded for 60 min posttreatment. Results: Nesfatin-1 induced cardiovascular responses in rats leading to pressor effect in MAP, and tachycardia following bradycardia in HR. Interestingly, ICV furegrelate, PGF2α-DA, or AH6809 pretreatment partially mitigated the cardiovascular effects revealed by nesfatin-1. Conclusion: The findings illuminate the role of nesfatin-1 in modulating MAP and HR through the central activation of specifically TXA2, PGF2α, PGE, and PGD from COX metabolites. Additionally, the study may also suggest the potential involvement of other central COX or LOX metabolites beyond these COX metabolites in mediating the cardiovascular effects produced by nesfatin-1.

The Relation between Plasma Nesfatin-1 Levels and Aggressive Behavior in Pit Bull Dogs.

Aggression is a prevalent and concerning behavioral issue in dogs. Pit Bull dogs, known for their high levels of aggression, are recognized as a focus of concern in society. In our study, we aimed to investigate the behavioral characteristics of Pit Bull dogs and explore the potential roles of peptides involved in the neurobiology of aggression. Initially, female, and male dogs underwent aggression tests, and their aggression levels were categorized. Plasma nesfatin-1, serotonin, oxytocin, and dopamine levels were quantified using ELISA, with blood samples collected after a 24 h fasting period and 2 h post-refeeding. Our findings indicate that aggression in Pit Bull dogs correlates with decreased plasma nesfatin-1, serotonin, and oxytocin levels, while dopamine levels increase. The study's findings indicate that fasted dogs exhibited lower plasma levels of nesfatin-1, serotonin, and dopamine, while plasma oxytocin levels were higher. Furthermore, while the research findings do not suggest a significant relationship between the severity of aggression and the gender of the dog, male Pit Bull breeds appear to have higher plasma nesfatin-1 and serotonin levels compared to their female counterparts. The study's findings demonstrate that nesfatin-1, serotonin, oxytocin, and dopamine play pivotal roles in Pit Bull dogs' aggression, indicating potential interactions among these neuropeptides at the central nervous system level.

The involvement of the central cholinergic system in the hyperventilation effect of centrally injected nesfatin-1 in rats.

We recently demonstrated that peripheral and central administration of nesfatin-1 in fasting and satiety states generate hyperventilation activity by increasing tidal volume (TV), respiratory rate (RR), and respiratory minute ventilation (RVM). The present study aimed to investigate the mediation of central cholinergic receptors effective in respiratory control in the hyperventilation activity of nesfatin-1. Besides this, we intended to determine possible changes in blood gases due to hyperventilation activity caused by nesfatin-1 and investigate the mediation of central cholinergic receptors in these changes. Intracerebroventricular (ICV) administration of nesfatin-1 revealed a hyperventilation response with an increase in TV, RR, RMV, and pO2 and a decrease in pCO2 in saturated Sprague Dawley rats. ICV pretreatment with the muscarinic receptor antagonist atropine partially blocked the RR, RMV, pO2, and pCO2 responses produced by nesfatin-1 while completely blocking the TV response. However, central pretreatment with nicotinic receptor antagonist mecamylamine blocked the respiratory and blood gas responses induced by nesfatin-1. The study's conclusion demonstrated that nesfatin-1 had active hyperventilation effects resulting in an increase in pO2 and a decrease in pCO2. The critical finding of the study was that activation of central cholinergic receptors was involved in nesfatin-1-evoked hyperventilation and blood gas responses.

The intermediary role of the central cyclooxygenase / lipoxygenase enzymes in intracerebroventricular injected nesfatin-1-evoked cardiovascular effects in rats.

That nesfatin-1 is a neuromodulatory peptide for the cardiovascular system is well documented. Several central receptors have been shown to mediate the cardiovascular effects of nesfatin-1. Immunohistochemistry and Western blot studies showed that nesfatin-1 activated the expression of the central cyclooxygenase (COX) -1, -2 and lipoxygenase (LOX). In addition, microdialysis study showed that nesfatin-1 increased the release of total prostaglandins and leukotrienes from the hypothalamus. The present study investigated whether the central COX and LOX enzymes have a direct mediating role in the MAP and HR responses of nesfatin-1. Intracerebroventricularly administered nesfatin-1 produced dose-dependent pressor and phasic HR responses in normotensive conscious rats Sprague Dawley. Central pretreatment with a COX1/2 inhibitor, ibuprofen, completely blocked the nesfatin-1-induced responses. However, central pretreatment with a nonselective LOX inhibitor, nordihydroguaiaretic acid, partially attenuated the cardiovascular responses induced by nesfatin-1. The results suggest that centrally administered nesfatin-1 activates the central enzymes COX and LOX, which may be involved in the cardiovascular responses as a novel central mechanism for nesfatin-1.

The mediation of central cyclooxygenase and lipoxygenase pathways in orexin-induced cardiovascular effects.

Previously it was reported that central orexin (OX) and arachidonic acid (AA) signaling pathways played an active role in the control of the cardiovascular system. It was also reported that they have exhibited their cardiovascular control role by using similar central or peripheral mechanisms. However, there has been no study demonstrating the interaction between OX and AA signaling pathways in terms of cardiovascular control. The current study was designed to investigate the possible mediation of the central cyclooxygenase (COX) and lipoxygenase (LOX) pathways in OX-induced cardiovascular effects in the rats. Intracerebroventricular injection of OX increased blood pressure and heart rate in a dose-dependent manner in normotensive male Sprague Dawley rats. Moreover, the microdialysis study revealed that intracerebroventricular injected OX caused a time-dependent increase in the extracellular total prostaglandin concentrations in the posterior hypothalamus. Interestingly, central pretreatment with a non-selective COX inhibitor, ibuprofen, or a non-selective LOX inhibitor, nordihydroguaiaretic acid, partially reversed pressor and tachycardic cardiovascular responses evoked by central administration of OX. In summary, our findings show that the central treatment with OX causes pressor and tachycardic cardiovascular responses along with an increase in posterior hypothalamic extracellular total prostaglandin concentrations. Furthermore, our results also demonstrate that central COX and LOX pathways mediate, at least in part, centrally administered OX-evoked pressor and tachycardic responses, as well.

Intracerebroventricularly injected nesfatin-1 activates central cyclooxygenase and lipoxygenase pathways.

Nesfatin-1 is a multifunctional neuropeptide having crucial autonomic roles. It is well known that nesfatin-1 collaborates with other central neuromodulatory systems, such as central corticotropin-releasing hormone, melanocortin, oxytocin, and cholinergic systems to show its autonomic effects. Central arachidonic acid cascade plays an important role to provide the homeostasis by exhibiting similar autonomic effects to nesfatin-1. Based on these similarities, the current study was designed to show the effects of intracerebroventricularly (ICV) injected nesfatin-1 on the hypothalamic arachidonic acid (AA) cascade. Immunochemistry and western blot approaches demonstrated that ICV administration of nesfatin-1 provokes an increase in the hypothalamic cyclooxygenase (COX) -1, -2 and lipoxygenase (LOX) protein expression. Moreover, the microdialysis study demonstrated that centrally injected nesfatin-1 increased the posterior hypothalamic extracellular AA products. In conclusion, these findings report that while nesfatin-1 is generating its autonomic effects, it also might be using central prostaglandins and leukotrienes by activating central COX and LOX pathways.

Modulation of arachidonic acid-evoked cardiorespiratory effects by the central lipoxygenase pathway.

We previously reported that intracerebroventricularly (ICV) injected arachidonic acid (AA) could produce pressor and bradycardic responses on the cardiovascular system and hyperventilation effect on the respiratory system by activating cyclooxygenase (COX). We also demonstrated that centrally injected AA-induced cardiovascular and respiratory responses were mediated by COX-metabolites, such as thromboxane A2 (TXA2), prostaglandin (PG) D, PGE, and PGF2α. Brain tissue is also able to express the lipoxygenase (LOX) enzyme and LOX-induced AA-metabolites. The current study was designed to investigate the possible mediation of the central LOX pathway in AA-induced cardiorespiratory effects in anesthetized rats. Central pretreatment with different doses of a non-selective LOX inhibitor, nordihydroguaiaretic acid (NDGA) (500 and 1000 µg; ICV) partially blocked the AA (0.5 µmol; ICV)-evoked pressor and bradycardic cardiovascular responses in male anesthetized Sprague Dawley rats. Pretreatment with different doses of NDGA (500 and 1000 µg; ICV) also reduced AA-induced hyperventilation responses, with an increase in tidal volume, respiratory rate and minute ventilation, in the rats. Moreover, AA-induced increasing pO2 and decreasing pCO2 responses were diminished by central NDGA pretreatment. In summary, our findings show that the central LOX pathway might mediate, at least in part, centrally administered AA-evoked cardiorespiratory and blood gases responses.