Ž . European Journal of Pharmacology 402 2000 77–85 www.elsevier.nlrlocaterejphar Mechanisms to prevent the toxicity of chronic neuroinflammation on forebrain cholinergic neurons Gary L. Wenk a, ) , Kristin McGann a , Andrea Mencarelli b , Beatrice Hauss-Wegrzyniak a , Piero Del Soldato c , Stefano Fiorucci b a Arizona Research Laboratories, DiÕision of Neural Systems, Memory and Aging, UniÕersity of Arizona, 384 Life Sciences North Building, Tucson, AZ 85724, USA b Clinica di Gastroenterologia ed Endoscopia DigestiÕa, Dipartimento di Medicina Clinica, Patologia e Farmacologia, UniÕersita degli Studi di Perugia, Perugia, Italy ` c NicOx, Sophia Antipolis, 1900 Route des Cretes, Valbonne, France ˆ Received 23 March 2000; received in revised form 10 July 2000; accepted 17 July 2000 Abstract Inflammatory processes may play an important role in the degeneration of basal forebrain cholinergic cells Alzheimer’s disease. We infused the proinflammagen lipopolysaccharide into the basal forebrain of young rats and determined whether the chronic administration Ž . of two novel non-steroidal anti-inflammatory drugs or a pan-caspase synthesis inhibitor, z-Val–Ala–Asp OMe -fluoromethyl ketone Ž . zVAD , could provide neuroprotection from the cytotoxic effects of the neuroinflammation. Chronic lipopolysaccharide infusions decreased choline acetyltransferase activity and increased the number of activated microglia within the basal forebrain region. The level of caspases 3, 8 and 9 was increased in ventral caudaterputamen. Non-steroidal anti-inflammatory drug therapy attenuated the toxicity of the inflammation upon cholinergic cells and reduced caspases 3, 8 and 9 activity in the caudaterputamen. zVAD treatment significantly decreased the levels of caspases 3, 8 and 9 but did not provide neuroprotection for the cholinergic neurons. These results suggest that prostaglandins contribute to the degeneration of forebrain cholinergic neurons in Alzheimer’s disease. q 2000 Elsevier Science B.V. All rights reserved. Ž . Keywords: Neuroinflammation; Rat ; Forebrain basal; Acetylcholine; Caspase; Non-steroidal anti-inflammatory drug 1. Introduction Alzheimer’s disease is characterized by specific neu- ropathological changes and a forebrain deficiency of Ž . acetylcholine Davis et al., 1999; Whitehouse et al., 1981 . The decline in the number of cholinergic cells within the basal forebrain may contribute to aspects of the cognitive Ž impairments associated with Alzheimer’s disease McGeer . et al., 1984; Muir, 1997 . Although chronic inflammatory processes may play an important role in the pathogenesis Ž of Alzheimer’s disease Akiyama et al., 2000; Aisen and Davis, 1994; Griffin et al., 1998; McGeer et al., 1989; ) Corresponding author. Tel.: q 1-520-626-2617; fax: q 1-520-626- 2618. Ž . E-mail address: gary@nsma.arizona.edu G.L. Wenk . McGeer and McGeer, 1999; Mrak et al., 1995; Rogers et . al., 1992; Rogers, 1995; Tan et al., 1999 , the mechanism underlying the degeneration of basal forebrain cholinergic cells is unknown. Alzheimer’s disease is associated with increased levels of inflammatory cytokines, such as inter- Ž leukin-1 and tumor necrosis factor-alpha Bauer et al., . 1991; Griffin et al., 1989; McGeer and McGeer, 1998 as Ž . well as various caspases Shimohama et al., 1999 that could contribute to the neurodegenerative process Ž . Akiyama et al., 2000; Blasko et al., 1997 . A potential role for neuroinflammation, and the specificity of its ef- fects upon cholinergic neurons, was suggested by a study that isolated antibodies from the sera of Alzheimer’s dis- ease patients that selectively recognized and destroyed basal forebrain cholinergic cells when injected into a rat Ž . brain Foley et al., 1988 . In addition, head trauma in humans is a significant risk factor for Alzheimer’s disease Ž . Rasmusson et al., 1995 and is associated with increased 0014-2999r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. Ž . PII: S0014-2999 00 00523-9