Evaluation of the mGluR2/3 agonist LY379268 in rodent models of Parkinson's disease.
The aim of the present studies was to examine the ability of a potent, systemically active, selective Group II mGlu receptor (mGluR2/3) agonist, 1R,4R,5S,6R-2-oxa-4-minobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) to provide both functional relief and neuroprotection in rodent models of Parkinson's disease (PD). In functional studies, intracerebroventricular administration of LY379268 (1, 5, 10, 20 nmol/2 microl) produced a dose-dependent increase in locomotor activity in the reserpine (5 mg/kg ip)-treated rat. In contrast, systemic administration of LY379268 (0.1, 1, 10 mg/kg ip) did not reverse reserpine-induced akinesia and failed to effect rotational behaviour 1 month after unilateral lesioning of the nigrostriatal tract by 6-hydroxydopamine (6-OHDA; 4 microg infused into the substantia nigra (SN)). In neuroprotective studies, animals were treated with LY379268 (10 mg/kg/day ip) either for 7 days following 6-OHDA injection into the SN (4 microg) or for 21 days following 6-OHDA injection into the striatum (10 microg) before measurement of tyrosine hydroxylase immunoreactivity in the striatum and/or SN as an index of neuroprotection. LY379268 provided some protection against nigral infusion of 6-OHDA and also some functional improvement and correction of dopamine turnover was observed. The compound also provided significant protection in the striatum and some protection in the SN against striatal infusion of 6-OHDA. These data suggest that activation of Group II mGlu receptors can provide some protection in models of PD, while their role in providing functional improvement is less clear.
Lilly Research Centre, Eli Lilly and Co. Ltd., Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK.
Tracey K
TK
Murray
Marcus J
MJ
Messenger
Mark A
MA
Ward
Sandra
S
Woodhouse
David J
DJ
Osborne
Susan
S
Duty
Michael J
MJ
O'Neill
D000596:Amino Acids / Q000627:therapeutic use*; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use*; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000473:pathology / Q000502:physiology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012110:Reserpine; D013239:Stereotyped Behavior / Q000187:drug effects; D013378:Substantia Nigra / Q000473:pathology / Q000502:physiology; D013563:Sympathectomy, Chemical; D013565:Sympatholytics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000596:Amino Acids; D000978:Antiparkinson Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; D013565:Sympatholytics; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D012110:Reserpine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase