Current Pharmaceutical Design, 2003, 8, 99-110 1 1381-6128/03 $35.00+.00 © 2003 Bentham Science Publishers Ltd. Annelid Neuroimmune System Christophe Lefebvre and Michel Salzet * Laboratoire de Neuroimmunologie des Annélides, UMR CNRS 8017, SN3, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq Cedex, France Abstract : Neuropeptides have been found in nervous central or immune systems of Annelids. Since these signaling molecules are found free in the hemolymph, they are considered as hormones. Hormonal processes along with enzymatic processing similar to that found in vertebrates occur in annelids. Furthermore, amino acid sequence determination of annelids precursor gene products reveals the presence of the respective peptides that exhibit high sequence identity to their mammalian counterparts. Nevertheless, specific neuropeptides to annelids or invertebrates have also been in these animals. These peptides are flanked by potential proteolytic signal sites for the various known enzymes confirming that annelids neuropeptide precursors are processed in a similar manner to that described in mammals i.e. implicating prohormone convertase enzymes. 1. INTRODUCTION Neuropeptides are widespread and play a major role in the animal kingdom, including in protozoa. The similar amino acid sequences of some of the neuropeptides, i.e., oxytocin/vasopressin, angiotensins, in vertebrates and in invertebrates demonstrate that they are stable and old in evolutionary terms. These signaling peptides seem to have appeared before that of a primitive nervous system, suggesting that they were first implicated in intercellular communication [1]. Therefore, they may have evolved from a small number of signaling proteins encoded by ancestral genes that have been conserved and amplified over time [1]. 2. WHAT CONSTITUTES A NEUROENDOCRINE SYSTEM? In vertebrates, this system is based on chemical signaling between neural and endocrine structures. Final outcomes may be realized via the chemical messengers traveling from circulatory conduits to their specific target sites. This process may, in part, rely on neurosecretion of the signaling molecules [2]. The complexity of this system can be visualized quickly when one considers its operating regulations that result from both classical neurotransmitters, cytokines, growth factors and hormones neuroendocrine, autocrine and paracrine communications. Apart from a neuroendocrine system also exists a neuroimmune communication, which consists to a reciprocal signaling between neuroendocrine and immune cells which use the same molecules to coordinate their activity, i.e., adrenocorticotropin ACTH [3]. We have recently *Address correspondence to this author at the Laboratoire de Neuroimmunologie des Annélides, UMR CNRS 8017, SN3, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq Cedex, France; E-mail: michel.salzet@univ-lillel.fr demonstrated that neurovascular regulation [4] of neurosecretion occurs in rat median eminence fragments via a nitric oxide mediated process [5]. Thus, our concept of a neuroendocrine system is constantly growing given its complexity but may be simply summarized as the result of bi-directional communications between neural and endocrine structures over a distance greater than that occurring by synaptic communication. 3. DO ANNELIDS HAVE A NEUROENDOCRINE SYSTEM? Annelids neural tissues do not contain anatomical correlates of hypothalamus or pituitary. However, they possess localized ganglionic regions rich in mammalian-like neuroendocrine signaling molecules e.g. angiotensins [6-8], oxytocin/vasopressin peptide family [7], opioids [9-12] (tables 1 and 2). Furthermore, these molecules appear free in the animals’ hemolymph, demonstrating distant signaling [13-15] via several target tissues [15], including immune cells [16-20]. Thus, the fact that a classical closed conduit system to carry signaling molecules does not exist in Annelids should not detract from an endocrine presence because the baseline functioning of the system depends on distance between the origin of a signal molecule and its target tissue/receptor. 4. ARE NEUROENDOCRINE SIGNALING MOLECULES IN ANNELIDS AND VERTEBRATES SIMILAR? This question represents an important aspect regarding the existence of an Annelids neuroendocrine system. Among the 30 neuropeptides isolated, so far, in annelids (Tables 1 and 2), the most part already sequenced are related to the ones previously isolated in vertebrates. They can be divided into 4 groups of signaling molecules i.e. the angiotensins,