Improvement of Mitochondrial Function by Paliperidone Attenuates Quinolinic Acid-Induced Behavioural and Neurochemical Alterations in Rats: Implications in Huntington's Disease

被引:25
作者
Mishra, Jitendriya [1 ]
Kumar, Anil [1 ]
机构
[1] Panjab Univ, UGC CAS, Univ Inst Pharmaceut Sci, Div Pharmacol, Chandigarh 160014, India
关键词
Apoptosis; BDNF; Biogenic amines; Mitochondrial respiration; Neuroinflammation; PRENATAL IMMUNE ACTIVATION; DOPAMINERGIC-NEURONS; NEUROTROPHIC FACTOR; PARKINSONS-DISEASE; BRAIN MITOCHONDRIA; PREFRONTAL CORTEX; ANIMAL-MODELS; VALPROIC ACID; RISPERIDONE; STRIATUM;
D O I
10.1007/s12640-014-9469-9
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Quinolinic acid (QA)-induced neurotoxicity involves a cascade of events such as increased calcium concentration in cytoplasm, exhaustive ATP depletion, oxidative stress, as well as selective GABAergic, dopaminergic, and cholinergic neuronal death. Clinical data hint towards the connection between signalling of dopaminergic system and efficient amelioration of chorea following a tetrabenazine administration in Huntington's disease patients. Therefore, the present study has been designed to explore the neuroprotective potential of paliperidone, an active metabolite of risperidone (a dopaminergic antagonist) against QA-induced neurotoxicity and related complications in rats. QA (200 nmol) was administered bilaterally to the striatum over a period of 2 min by means of a 28-gauge stainless steel needle attached to a Hamilton syringe. The study protocol involves seven treatment groups (n = 12): na < ve, sham, control (QA), paliperidone (0.5, 1 and 2 mg/kg) and paliperidone (2) per se. Single bilateral intrastriatal injection of QA (200 nmol/2 mu l saline) significantly caused motor incordination, memory impairment, oxidative damage, decrease in biogenic amines levels, cellular alterations (TNF-alpha, IL-6, PGE2, PGF2 alpha, caspase-3, BDNF, mitochondrial function) and damage of striatal neurons compared to the sham treatment. Treatment with paliperidone (0.5, 1 and 2 mg/kg) for 21 days significantly attenuated the QA-induced behavioural (motor and memory function), neurochemical (antioxidant enzymes and biogenic amines) and cellular alterations, as well as striatal neurodegeneration. The study indicated that modulation of dopaminergic pathway by paliperidone treatment could be a useful approach in the management of motor and memory abnormality in HD patients.
引用
收藏
页码:363 / 381
页数:19
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