title: Improvement of mitochondrial NAD(+)/FAD(+)-linked state-3 respiration by caffeine attenuates quinolinic acid induced motor impairment in rats: implications in Huntington's disease.
abstract: BACKGROUND
  Chronic quinolinic acid (QA) lesions in rats closely resemble Huntington's disease like conditions. Oxidative stress and mitochondrial dysfunction have long been implicated in the neurotoxic effects of QA acting through N-methyl-d-aspartate (NMDA) receptors. Reports suggest that inhibition of adenosine A2A receptor function elicits neuroprotective effect in QA induced neurotoxicity in rats. Caffeine, a preferential A2A receptor antagonist imitates antioxidant like actions and exerts neuroprotective effects in various neurodegenerative conditions. Thus, the present study was designed to evaluate the neuroprotective effects of caffeine against QA induced neurotoxicity in rats.
  
  
  METHODS
  In the present study, QA (200nmol/2μl saline) has been administered bilaterally to the striatum of rats followed by chronic caffeine (10, 20 and 40mg/kg) administration for 21 days. Motor performance of the animals was evaluated in weekly intervals and subsequently after 21 days, the animals were sacrificed and measurement of mitochondrial complexes activity, respiration rate and endogenous antioxidant levels were carried out in the striatal region.
  
  
  RESULTS
  Single intrastriatal QA administration resulted in drastic reduction in body weight, marked motor impairment (decreased total locomotor activity in actophotometer and impaired grip strength in rotarod), increased oxidative stress, impaired mitochondrial complexes activities and decreased state 3 respiration (NAD(+)/FAD(+)-linked) in rats. However, chronic treatment of caffeine for 21 days significantly attenuated the QA induced behavioural, biochemical and mitochondrial alterations displaying neuroprotective efficacy.
  
  
  CONCLUSIONS
  The study highlights the possible involvement of A2A receptor antagonism in the neuroprotective effect of caffeine against QA induced mitochondrial dysfunction and oxidative stress in rats.
authors.affiliation: University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh, India.
authors.forename: Jitendriya
authors.initials: J
authors.lastname: Mishra
authors.affiliation: University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh, India. Electronic address: kumaruips@yahoo.com.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D006816:Huntington Disease / Q000188:drug therapy* / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009243:NAD / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects*; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D009243:NAD; D005182:Flavin-Adenine Dinucleotide; D002110:Caffeine; D017378:Quinolinic Acid
keywords: Adenosine A2A receptor; Caffeine; Mitochondria; Oxidative stress