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Drug-Induced Dyskinesia

 

Dyskinesia is a potentially irreversible movement disorder associated with long-term administration of neuroleptic drugs. Iminodipropionitrile (IDPN) is a neurotoxic compound that produces motor syndrome in rodents, which resembles human idiopathic dyskinesia and has been used as an experimental model for drug-induced dyskinesia. IDPN-induced dyskinesia is also termed as ECC (excitation, chorea, circling) syndrome and characterized by repetitive head movements, retropulsion, circling, back walking, hyperactivity and swimming deficits. Because of the unique array of neurobehavioral abnormalities, IDPN is considered as one of the most suitable compounds for validation of functional observational battery (FOB) and motor activity for screening of neurotoxic drugs. The mechanism of IDPN-induced dyskinesia appears to be complex and multifactorial. We therefore performed extensive research to understand the potential mechanisms involved in the pathogenesis of IDPN-induced neurotoxicity.

 

 

Figure. Degeneration of sensory epithelium and vestibular hair cells by IDPN. (A) Crista ampullaris of a control rat (B) IDPN treated.

 

We demonstrated the protective effects hydrocortisone [1], metoclopramide [2], sodium benzoate [3], cysteamine [4], deoxyglucose [5] and salicylate [6] on IDPN-induced movement disorders in rats. These drugs reversed the adverse effects of IDPN on oxidative stress and/or vestibular hair cell degeneration. On the other hand, advancing age [7] as well as gentamicin [8], aminoguanidine [9], proglumide [10] and N-ethylmaleimide [11] were found to enhance the neurotoxicity of IDPN. The tolerance to IDPN-induced toxicity in diabetic rats was attributed to diminished dopaminergic activity and rapid clearance of this drug in diabetic rats [12]. Altogether, our findings showed that IDPN-induced motor deficits are associated with increased oxidative stress, alteration in neurotransmitters and vestibular hair cell degeneration in rats; modification of these targets by drugs alters the course of IDPN-induced neurotoxicity.

  1. Mohamed T, Khan HA, Al Moutaery K, Al Deeb S. Protective effect of hydrocortisone on iminodipropionitrile-induced neurotoxicity in rats. Basic Clin Pharmacol Toxicoal 2007; 100: 176-181.  
  2. Khan HA, Al Moutaery K, Al Deeb S, Mohamed T. Metoclopramide attenuates iminodipropionitrile-induced oxidative stress and neurobehavioral toxicity in rats. Pharmacol Biochem Behav 2004; 79: 555-561.
  3. Mohamed T, Khan HA, Al Moutaery K, Al Deeb S. Sodium benzoate attenuates iminodipropionitrile-induced behavioral syndrome in rats. Behav Pharmacol 2004; 15: 585-588.
  4. Mohamed T, Al Deeb S, Al Moutaery K, Khan HA. Cysteamine attenuates iminodipropionitrile (IDPN) induced dyskinesia in rats. Intern J Neurosci 1995; 83: 165-175.
  5. Mohamed T, Khan HA, Al Moutaery K, Al Deeb S. Protection by 2-Deoxy-D-glucose against b,b¢-iminodipropionitrile-induced dyskinesia in mice. Exp Neurol 1999; 158: 229-233.
  6. Mohamed T, Khan HA, Al Moutaery K, Al Deeb S. Attenuation of iminodipropionitrile-induced behavioral syndrome by sodium salicylate in rats. Pharmacol Biochem Behav 2002; 73: 647-654.
  7. Khan HA, Al Deeb S, Al Moutaery K, Mohamed T. Influence of age on iminodipropionitrile-induced vestibular and neurobehavioral toxicities in rats. Exp Toxicol Pathol 2003; 55: 181-186.
  8. Al Deeb S, Al Moutaery K, Khan HA, Mohamed T. Exacerbation of iminodipropionitrile induced behavioral toxicity, oxidative stress and vestibular hair cell degeneration by gentamicin. Neurotoxicol Teratol 2000; 22: 213-220.
  9. Mohamed T, Khan HA, Al Deeb, Al Moutaery K. Nirtic oxide synthase inhibitor aminoguanidine potentiates iminodipropionitrile induced neurotoxicity in rats. Neuroscience Lett 1999; 276: 49-52.
  10. Mohamed T, Khan HA, Zehra R, Al Moutaery K, Al Deeb S. Proglumide, a cholecystokinin receptor antagonist exacerbates b,b¢- iminodipropionitrile-induced dyskinesia in rats. Neurotoxicol Teratol 1998; 20; 571-579.
  11. Mohamed T, Al Deeb S, Al Moutaery K, Khan HA (1997) Effect of sulfhydryl blocking agent on iminodipropionitrile-induced dyskinesia in rats. Neurosciences J. 2 (3), 152-157.
  12. Mohamed T, Khan HA, Al Moutaery K, Al Deeb S. Tolerance to b,b¢-iminodipropionitrile-induced neurobehavioral and vestibular toxicity in diabetic rats. J Appl Toxicol 1999; 19: 93-99.

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