Evaluation of behavioural effects of a selective NMDA NR1A/2B receptor antagonist in the unilateral 6-OHDA lesion rat model.
The degeneration of the dopaminergic nigrostriatal pathway in Parkinson's disease (PD) is associated with altered transmission at striatal NMDA receptors containing NR2B subunits. We investigated a potential novel therapeutic compound, 4-trifluoromethoxy-N-(2-trifluoromethyl-benzyl)-benzamidine (BZAD-01), a selective NMDA NR1A/2B receptor antagonist for PD and compared it with levodopa, the standard treatment for PD. This study also evaluated whether combining levodopa and BZAD-01 gave better improvements of parkinsonian symptoms. Parkinsonism was induced by microinjection of the toxin, 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) of 40 Sprague-Dawley rats. Parkinsonism and the efficacy of drugs were assessed using a battery of behavioural tests including balance beam, apomorphine-induced rotation, body axis bias or "curling", head position bias and disengage sensorimotor latency test. Immunohistochemistry was performed on post-mortem tissue to estimate the loss of dopaminergic neurons. The main effects were that BZAD-01 co-administration prevented chronic levodopa-induced potentiation of apomorphine rotation. However levodopa-treated rats were slower than either controls or BZAD-01-treated rats in the locomotor test. The improvement in the apomorphine rotation test suggests that BZAD-01 may be a useful adjunct to levodopa monotherapy.
Warraich
S T
ST
Department of Pharmacology, Bosch Institute and School of Medical Sciences, University of Sydney, NSW 2006, Australia.
Allbutt
H N
HN
Billing
R
R
Radford
J
J
Coster
M J
MJ
Kassiou
M
M
Henderson
J M
JM
D000284:Administration, Oral; D018663:Adrenergic Agents / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001550:Benzamidines / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D007150:Immunohistochemistry; D007980:Levodopa / Q000008:administration & dosage / Q000627:therapeutic use; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine / Q000008:administration & dosage / Q000633:toxicity*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C539201:4-trifluoromethoxy-N-(2-trifluoromethylbenzyl)benzamidine; D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D001550:Benzamidines; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine