Toxicological Sciences 66, 148-158 (2002)
Copyright © 2002 by the Society of Toxicology
NEUROTOXICOLOGY |
Sensorimotor Deficit and Cholinergic Changes following Coexposure with Pyridostigmine Bromide and Sarin in Rats
,
* Department of Pharmacology and Cancer Biology and
Department of Medicine (Neurology), Duke University Medical Center, Durham, North Carolina 27710; and
Veterans Administration Medical Center, Durham, North Carolina
A myriad of neurological symptoms including muscle and joint pain, ataxia, chronic fatigue, headache, and difficulty in concentration have been reported by Persian Gulf War (PGW) veterans. A large number of these veterans were prophylactically treated with pyridostigmine bromide (PB) and possibly exposed to sarin. In the present study we investigated the effects of PB and sarin, alone and in combination, on sensorimotor performance and the central cholinergic system of rats. Male Sprague-Dawley rats were treated with PB (1.3 mg/kg, 15 daily doses, oral) and sarin (50, 75, 90, and 100 µg/kg, single im dose on day 15), alone and in combination. The animals were evaluated for postural reflexes, limb placing, orienting to vibrissae touch, incline plane performance, beam-walk time, and forepaw grip time 7 and 15 days following treatment with sarin. Treatment with either PB or sarin alone resulted in significant sensorimotor impairments. Coexposure to sarin and PB resulted in significant sensorimotor deficits that worsened over time. By 15 days following sarin treatment, plasma butyrylcholinesterase (BChE) activity returned to normal levels in the animals treated with sarin alone, whereas in the animals exposed to PB or PB plus sarin, there was an increase in the enzyme activity. Cortical acetylcholinesterase (AChE) activity remained inhibited in the animals treated with sarin alone and in combination with PB. Muscarinic acetylcholine receptor (m2 mAChR) ligand binding with [3H]AFDX-384 in cortex and brain stem showed significant increases (
120–130% of control) following coexposure to PB and sarin at higher doses. To evaluate the potential of PB for augmentation or inhibition of the toxicity induced by acute sarin exposure, the animals were exposed to either 10 or 100 µg/kg sarin (single im injection) with or without pretreatment with PB, and sacrificed 3 h after treatment with sarin. Pretreatment with PB offered slight protection in the plasma as well as brain regional enzyme activities. Pretreatment with PB did not have any effect on sarin-inhibited brain regional AChE activity following treatment with 100 µg/kg sarin. These results show that prophylactic treatment with PB offers some degree of protection in peripheral cholinesterase. Furthermore, these results show that treatment with either sarin or PB alone resulted in sensorimotor impairments, while coexposure to high doses of sarin with PB caused an exacerbated deficit.
Key Words: sarin; pyridostigmine bromide; PB; acetylcholinesterase; muscarinic acetylcholine receptor; neurotoxicity; combined exposure; sensorimotor; Gulf War.
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