Altered levels of neuropeptides characterize the brain of lupus prone mice Luisa Bracci-Laudiero a, b, * , Luigi Aloe b , Thomas Lundeberg a , Elvar Theodorsson c , Carina Stenfors a a Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden b Institute of Neurobiology C.N.R., Viale Marx 15, 00137 Rome, Italy c Division of Clinical Chemistry, Faculty of Health Sciences, Linko È ping, Sweden Received 26 July 1999; received in revised form 9 September 1999; accepted 10 September 1999 Abstract It has been reported that more than 50% of lupus patients show various forms of neurological de®cits including impaired cognitive functions and psychiatric disorders. Using an animal model of lupus we investigated the production of neuropeptides in the brain of NZB/W F1 female hybrid mice and its parental strain NZB and NZW. Our results indicate that the alteration in learning and memory described in lupus mice are paralleled by a decrease in calcitonin gene-related peptide, substance P and neuropeptide Y (NPY) levels in the hippocampus and a signi®cant decrease of NPY in the cortex. These ®ndings are interesting in the light of previously reported results suggesting that these neuropeptides can play an important role in cognitive functions. We also observed a decrease of NPY and vasoactive intestinal polypeptide levels in the hypothalamus of lupus prone mice and these changes may be related to the disregulation of the hypotha- lamus-pituitary-adrenal axis observed in lupus prone mice. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Substance P; Calcitonin gene-related peptide; Vasoactive intestinal polypeptide; Neuropeptide Y; Systemic lupus erythema- tosus; Brain; NZB/W F1 mice Systemic lupus erythematosus (SLE), a multi-systemic autoimmune disease primarily affecting women, is charac- terized by a hyperactivation of B-cells, increased production of autoantibody, autoimmune complexes and in¯ammatory cytokines. Effects on the central nervous system (CNS) have been reported in more than 50% of SLE patients showing neurologic de®cits such as cognitive dysfunction, seizures, and psychiatric disorders including psychosis, depression and anxiety [5,8]. Although the abnormal production of antineuronal and antiphospholipid antibodies [3,16] seems to be partly responsible for some of the neurological symp- toms in SLE, the mechanisms leading to altered nervous system functions in SLE are still unclear. The pathogenesis of cerebral lupus may be studied using murine models such as NZB/W F1, obtained from the mating of NZB mice, the ®rst described model of autoimmune disease [9], with the phenotypically normal NZW. The NZB/W F1 female hybrids spontaneously develop an autoimmune disease closely resembling human SLE [22]. As observed also in SLE patients, SLE prone mice present neurological impair- ments such as abnormal postural responses and persistent tremors [11], and changes in cognitive functions [25], which become more severe during the progress of the disease. In a previous study we described a signi®cant decrease in the levels of nerve growth factor (NGF) in different areas of the brain of SLE mice at 8 months of age, when disease symptoms are well-established [2]. Since NGF regulates neuropeptide expression [14,24], we hypothesized that a modi®cation in NGF production can affect neuropeptide expression in SLE mice. Neuropeptides are widely distrib- uted through the brain and numerous studies indicate that they may participate in several physiological processes including pain sensation, memory, regulation of mood and neuroendocrine functions. It is therefore possible that modi®cations in the baseline concentration of neuropeptides in the brain can contribute to the behavioural alterations that characterize lupus prone mice. In order to evaluate whether the progression of SLE can be related to variation of neuropeptide synthesis in CNS, we analyzed the levels of substance P (SP), calcitonin gene- Neuroscience Letters 275 (1999) 57±60 0304-3940/99/$ - see front matter q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(99)00737-5 www.elsevier.com/locate/neulet * Corresponding author. Tel.: 139-068-609-0288; fax: 139-068- 609-0370. E-mail address: luisa@biocell.irmkant.rm.cnr.it (L. Bracci-Laudiero)