The novel sigma ligand JO 1994 protects against ischaemia-induced behavioural changes, cell death and receptor dysfunction in the gerbil.
To assess the effects of the novel sigma ligand JO 1994 on behavioural, histological and autoradiographical changes following global ischaemia, the Mongolian gerbil was used. Three experiments were carried out and in each case ischaemia was induced by bilateral carotid occlusion (BCO) for 5 min. In the first experiment we examined the effects of JO 1994 administered at doses of 0.25, 0.5 and 1 mg/kg i.p. 1 h before 5 min BCO on histological parameters 96 h after surgery. In the second experiment the effects of JO 1994 administered at doses of 2.5, 5, 10 and 20 mg/kg i.p. 1 h before 5 min BCO on locomotor activity 24, 48 and 72 h after surgery and on histological parameters 96 h after surgery was examined. In the third experiment the effects of JO 1994 (2.5 and 5 mg/kg i.p.), BMY 14802 (1 and 10 mg/kg i.p.) and MK-801 (2.5 mg/kg i.p.) administered 30 min, 6, 24, 48, 72, 96 and 120 h post-surgery on the densities of M1 and M2 muscarinic receptors in 35 brain regions, 7 days after surgery was examined. Results indicated that 5 min bilateral carotid occluded animals were hyperactive 24, 48 and 72 h after surgery. JO 1994 attenuated this hyperactivity. Extensive neuronal death was observed in the CA1 layer of the hippocampus in 5 min BCO animals 96 h after surgery. The low doses of JO 1994 (0.25, 0.5 and 1 mg/kg) had no effect on the ischaemia-induced cell death. However JO 1994 (2.5, 5, 10 and 20 mg/kg i.p.) protected against the neuronal death of cells in the CA1 layer (P < 0.01-0.03). There was a large loss of M1 and M2 receptors in the CA1 regions of the hippocampus. MK-801, BMY 14802 and JO 1994 provided significant (P < 0.01) protection against this ischaemia-induced receptor loss.
O'Neill
M
M
Department of Pharmacology, University College, Galway, Ireland.
Canney
M
M
Earley
B
B
Junien
J L
JL
Leonard
B E
BE
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000473:pathology*; D001923:Brain Chemistry / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology* / Q000523:psychology*; D016923:Cell Death / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005849:Gerbillinae; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009930:Organic Chemicals; D011743:Pyrimidines / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism*
D014151:Anti-Anxiety Agents; D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D009930:Organic Chemicals; D011743:Pyrimidines; D017480:Receptors, sigma; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; C102336:JO 1994; D011813:Quinuclidinyl Benzilate; D016291:Dizocilpine Maleate