Central mediators involved in the febrile response: effects of antipyretic drugs

Abstract

Fever is a complex signal of inflammatory and infectious diseases. It is generally initiated when peripherally produced endogenous pyrogens reach areas that surround the hypothalamus. These peripheral endogenous pyrogens are cytokines that are produced by leukocytes and other cells, the most known of which are interleukin-1β, tumor necrosis factor-α, and interleukin-6. Because of the capacity of these molecules to induce their own synthesis and the synthesis of other cytokines, they can also be synthesized in the central nervous system. However, these pyrogens are not the final mediators of the febrile response. These cytokines can induce the synthesis of cyclooxygenase-2, which produces prostaglandins. These prostanoids alter hypothalamic temperature control, leading to an increase in heat production, the conservation of heat, and ultimately fever. The effect of antipyretics is based on blocking prostaglandin synthesis. In this review, we discuss recent data on the importance of prostaglandins in the febrile response, and we show that some endogenous mediators can still induce the febrile response even when known antipyretics reduce the levels of prostaglandins in the central nervous system. These studies suggest that centrally produced mediators other than prostaglandins participate in the genesis of fever. Among the most studied central mediators of fever are corticotropin-releasing factor, endothelins, chemokines, endogenous opioids, and substance P, which are discussed herein. Additionally, recent evidence suggests that these different pathways of fever induction may be activated during different pathological conditions.

Central mediators of the zymosan-induced febrile response

“…The CRF/ET-1 pathway is not involved in i.a. zymosan-induced fever [24], indicating that the eOPs are not released through the CRF or ET-1 during the febrile response; instead, they appear to be released through cytokines, such as TNF-α and IL-6 [20,21].…”

“…eOPs and ET-1) induces fever independently of the prostaglandin synthesis, whereas substance P appears to act in concert with prostaglandins in the autocrine circuitry [15,21]. The CRF appears to be involved in both prostaglandin-dependent and -independent mechanisms (for review, see [21]). …”

Virtual screening and biological evaluation of novel antipyretic compounds

“…The prostaglandin E 2 (PGE 2 ) is the major eicosanoid produced in the central nervous system, during inflammation and fever in mammalians . However, previous efforts to reduce PGE 2 production relied on the inhibition of the enzyme cyclooxygenase (COX), which exists in two isoforms (COX‐1 and COX‐2) . In fact, the most recent antipyretic drugs (COX‐2 selective inhibitors) can induce damage to patients with cardiovascular pathologies, whereas non‐selective inhibitors are harmful to the gastrointestinal/renal system and to patients with hemorrhagic diseases, such as dengue .…”

Proinflammatory Cytokine Profile in Patients With Different Alpha-1-Antitrypsin Phenotypes

“…При действии патогена первыми начинают экспрессироваться основные эндогенные пиро-гены: IFNγ, TNFα, IL-1β и IL-6, активирующиеся при любом островоспалительном процессе [6]. В частности, сигаретный дым запускает мест-ную продукцию TNFα, IL-6 и IL-8 в дыхатель-ных путях [7,8].…”