Neuroprotective effects of a selective N-methyl-D-aspartate NR2B receptor antagonist in the 6-hydroxydopamine rat model of Parkinson's disease.
1. Current pharmacotherapies for the treatment of Parkinson's disease (PD) are largely symptomatic and do not attenuate the characteristic nigral (dopamine) cell loss. 2. Using the 6-hydroxydopamine (6-OHDA) rat model of PD, we investigated the novel, potentially neuroprotective compound BZAD-01, which is an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist selective for the NR2B subunit. 3. Forty female Sprague-Dawley rats were pretreated with either 10 mg/kg BZAD-01 or vehicle (5% sucrose and 0.1% ascorbate) in their drinking water for 11 days prior to and for 3 days following 6-OHDA surgery. During surgery, rats received an injection of either a toxic dose of 16 microg 6-OHDA or a non-toxic dose of 1 microg 6-OHDA (sham) into the medial forebrain bundle. A series of behavioural tests, including curling (measuring body axis bias), head position bias and narrow beam, was performed fortnightly for 8 weeks after surgery to assess the effects of BZAD-01 pretreatment on parkinsonism. Drug-induced rotational asymmetry was also assessed just before rats were killed. Post-mortem immunohistochemistry was performed to quantify the degree of nigral dopamine cell loss. 4. Pretreatment of 6-OHDA-lesioned rats with BZAD-01 significantly reduced the amount of dopamine cell loss and significantly improved all behavioural measures. Furthermore, there was no significant difference in any of the behavioural measures between lesioned rats pretreated with BZAD-01 and rats that underwent sham surgery.
Leaver
K R
KR
Department of Pharmacology, Bosch Institute and School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia.
Allbutt
H N
HN
Creber
N J
NJ
Kassiou
M
M
Henderson
J M
JM
D000818:Animals; D001550:Benzamidines / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology
C539201:4-trifluoromethoxy-N-(2-trifluoromethylbenzyl)benzamidine; D001550:Benzamidines; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016627:Oxidopamine