356 Short report Pentoxifylline attenuates iminodipropionitrile-induced behavioral abnormalities in rats Saeed Al Kadasah a , Ahmad Al Mutairy a , Mairaj Siddiquei a , Haseeb Ahmad Khan b , Ibrahim Abdulwahid Arif b , Khalaf Al Moutaery a and Mohammad Tariq a This investigation was undertaken to study the effect of pentoxifylline (PTX) on iminodipropionitrile (IDPN)-induced behavioral abnormalities [excitation with choreiform and circling movements (ECC) syndrome] in rats. The animals were intraperitoneally injected with IDPN (100 mg/kg) daily for 7 days. PTX was administered daily 30 min before IDPN in the doses of 25, 50, and 100 mg/kg for 9 days. The animals were observed for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex, and contact inhibition of the righting reflex. The onset of ECC syndrome was observed on day 8 in the group treated with IDPN alone; all animals in this group became dyskinetic on day 10. Co-treatment with PTX dose dependently delayed the onset time and significantly reduced the incidence and severity of IDPN-induced ECC syndrome; high dose of PTX completely inhibited the abnormal behavioral signs in IDPN-treated rats. Administration of IDPN caused significant depletions in cerebral glutathione and vitamin E levels. Treatment with PTX dose dependently attenuated IDPN-induced oxidative stress in rats. The beneficial effects of PTX against IDPN toxicity may be attributed to its antioxidant and anti-inflammatory properties. Behavioural Pharmacology 20:356–360  c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. Behavioural Pharmacology 2009, 20:356–360 Keywords: behavioral syndrome, iminodipropionitrile, inflammation, neurotoxicity, oxidative stress, pentoxifylline, rat a Neuroscience Research Group, Armed Forces Hospital and b Prince Sultan Research Chair for Environment and Wildlife, College of Sciences, King Saud University, Riyadh, Saudi Arabia Correspondence to Mohammad Tariq, PhD, FRCPath, FRSC, Senior Consultant and Director of Research, Armed Forces Hospital, PO Box 7897, Riyadh 11159, Saudi Arabia E-mail: rkh_research@yahoo.com Received 30 March 2009 Accepted as revised 30 April 2009 Introduction The occupational and environmental exposure to synthetic nitriles because of their extensive usage in industries such as fibers, plastics, dyes, resins, and pharmaceuticals has raised concerns about their harm- ful effects with potential relevance to human health (Ahmed and Trieff, 1983; Guirguis et al., 1984; Bergmark, 1997; Perbellini et al., 1998). There are several nitriles of industrial application including iminodipropionitrile (IDPN), acrylonitrile, crotonitrile, and allylnitrile that are known to produce motor deficits in experimental animals (Tanii et al., 1991; Gagnaire et al., 1998; Balbuena and Llorens, 2001; Khan et al., 2004; Tariq et al., 2007). However, among the aforementioned nitriles, IDPN has been most extensively studied for its neurotoxic effects in experimental animals since the discovery that it produces a permanent behavioral syndrome in rodents, characterized by repetitive head movements, retropulsion, circling, hyperactivity, and swimming deficits (Delay et al., 1952; Selye, 1957). IDPN-induced behavioral syndrome is commonly known as excitation with choreiform and circling movements (ECC) syndrome (Selye, 1957). Earlier studies, based on neuropathological obser- vations, showed IDPN-induced axonal swellings and neurofilamentous accumulation in the brainstem, spinal cord, and peripheral nervous system (Chou and Hartman, 1964; Griffin et al., 1982). Llorens et al. (1993a) observed dose-dependent elevations of glial fibrillary acidic protein (GFAP) in the pons medulla, midbrain, cerebral cortex, and olfactory bulb of rats exposed to IDPN, suggesting the involvement of the central nervous sys- tem in IDPN-induced neurotoxicity. Peele et al. (1990) showed learning and memory deficits in rodents treated with IDPN, supporting a role of higher levels of central nervous system in IDPN neurotoxicity. Recently, the behavioral abnormalities caused by IDPN have been associated with the dose-dependent and time-dependent degeneration of vestibular sensory hair cells in IDPN- treated animals (Llorens et al., 1993b; Khan et al., 2004; Tariq et al., 2007). The mechanism of IDPN-induced neuropathological changes and vestibular hair cell degeneration is obscure. However, numerous studies point towards a pivotal role of oxygen-derived free radicals (ODFR) in the neurobehavioral toxicity of this nitrile compound (Lohr et al., 1998; Wakata et al., 2000; Nomoto, 2004; Tariq et al., 2002, 2004). Pentoxifylline (PTX), a methylxanthine derivative and phosphodiesterase inhibitor, has recently gained 0955-8810  c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FBP.0b013e32832ec5ea