Inflammation-induced neurotropin biosynthesis-effects of antiphlogistic drugs

In patients, as well as in experimental animals, the concentration of nerve growth factor (NGF) is significantly increased in inflamed tissues. Blockade of endogenous NGF prevents inflammatory hyperalgesia demonstrating that NGF is an important mediator responsible for increased pain perception in inflamed tissues. Furthermore, there are good reasons to assume that an inflammation-induced increase of NGF concentrations in visceral organs, e.g. the bronchial system will lead to increased sensitivity of afferent nerve endings to irritant stimuli. Less is known about the response to inflammation of related neuronal growth factors (neurotrophins) and their role in inflammation. The existence of specific binding sites for several neurotrophins on neuronal and non-neuronal cells strongly suggests such a role. Of particular relevance seems the induction of brain-derived neurotrophin (BDNF) in cell bodies of afferent neurons projecting to inflamed areas. In spite of the known importance of NGF as mediator of inflammatory hyperalgesia there is little known about the effects antiphlogistic drugs might have on inflammation-induced NGF expression., Conceivably, attenuation of inflammatory symptoms (achieved e.g. by blockade. of prostanoid biosynthesis) is not necessarily accompanied by inhibition of the NGF response and its consequences on neuronal phenotype. However, available evidence suggest that some drugs used in inflammatory diseases can in fact attenuate the inflammation-induced NGF increase, an effect that may contribute to the therapeutic value. The first objective of this research project is to investigate the time course and pattern of neurotrophin (NGF, BDNF, NT-3) biosynthesis in the skin and bronchial mucosa, as well as the BDNF response in cell bodies of afferent neurons to mast cell-mediated allergic inflammation. We assume this type of experimental inflammation to be of special interest, not only because of its particular relevance in the respiratory system and skin, but also because mast cells constitute a major source of NGF (and possibly other neurotrophins). Other inflammatory stimuli which are known to cause NGF upregulation will be used for comparison. Based on these initial results, the second objective of this study is to investigate the effects of selected antiphlogistic drugs on the inflammation- induced increase of NGF in the skin and bronchial mucosa, and on BDNF expression in cell bodies of afferent neurons comparing the antiphlogistic drug potency with its potency to inhibit the NGF/BDNF response. We expect that the results of this study will provide novel information about the neurotrophin biosynthesis in allergic inflammation of the skin and respiratory tract, and widen our knowledge about the mode of action of antiphlogistic drugs.

It has been known that nerve growth factor (NGF), a peptide belonging to the neurotrophin family is formed in inflamed peripheral tissue. This rise in the local concentration of NGF affects primary afferent neurons projecting to the inflamed area, and subsequently leads to increased sensitivity of the neuronal afferent pathways. This increased sensitivity is one factor involved in the development of symptoms experienced in inflammatory disease such as hyperalgesia in somatosensory and hyperreflexia in the visceral system. It seems of interest, therefore, that we have obtained results suggesting that transmitters released from peripheral branches of afferent neurons stimulate NGF formation in the innervated tissue, thus indicating the existence of a positive feed-back mechanism regulating NGF biosynthesis. Since there was only very little known about the effects on NGF formation of drugs used in the treatment of inflammation, a main focus of this research project has been to determine possible pharmacological interference with inflammation-induced neurotrophin biosynthesis. Our experimental studies have provided results that may contribute to a better understanding of the mode of action of anti-inflammatory drugs. These results include the demonstration that inhibition of prostaglandin biosynthesis and acute inflammatory symptoms by aspirin-like drugs has no appreciable effect on the inflammation-induced overproduction of NGF, suggesting that even in the absence of overt inflammatory symptoms, sensitization of afferent pathways can take place. On the other hand, drugs that are not primarily associated with anti-inflammatory activity, proved highly effective in our experiments. Here it seems worth mentioning that morphine (a prototypical CNS analgesic) as well as beta adrenoceptor agonists (drugs commonly used in the treatment of asthmatic disease) have - depending on the type of inflammatory response - the potential to reduce the rise in tissue NGF, an observation that may have bearings on discussions about anti-inflammatory therapy.