Global Ischemia In Gerbils Research Articles

Neuroprotective effects of lamotrigine in global ischemia in gerbils. A histological, in vivo microdialysis and behavioral study

A sudden surge in the release of glutamate is currently believed to be an important initiating step in neuronal damage due to an ischemic insult. In this experiment, we tested the efficacy of neuroprotection with lamotrigine, a novel antiepileptic drug that blocks voltage gated sodium channels and inhibits the ischemia-induced release of glutamate in the gerbil forebrain model of cerebral ischemia. The medication was administered 30 min before and 30 min after the insult in two groups of animals. Histological assessment of neuronal damage was evaluated at 7 and 28 days after the ischemic insult. Animals evaluated at 28 days also underwent behavioral testing. Microdialysis was used in the same model to study the response of ischemia-induced glutamate in saline treated controls versus animals treated with lamotrigine 20 min before the insult. There was highly significant neuronal protection in animals who were treated with lamotrigine either before or after the insult. Protection was seen both at 7 and 28 days after the insult. Behavioral testing also showed significantly better recovery in both sets of animals in comparison to the saline-treated group. Microdialysis confirmed a significant attenuation of the ischemia-induced glutamate surge when compared to the saline-treated animals. Our morphological, behavioral and microdialysis experiments show that lamotrigine offers significant neuroprotection from the effects of transient forebrain ischemia in gerbils. Neuroprotection with post-ischemic therapy probably depends on preserving the capacity of the sodium/calcium exchanger to reduce intracellular calcium concentrations or persistent `toxicity' of glutamate in the reperfusion period on the already `primed' injured neurons. These concepts need further study.

Lack of efficacy of 5‐HT2A receptor antagonists to reduce brain damage after 3 minutes of transient global cerebral ischaemia in gerbils

Stimulation of the 5-HT2A receptors by serotonin has been reported to exert an excitatory effect on neocortical neurons in rats and mice, to facilitate ischaemia-induced release of excitatory amino acids and to mediate the vasomotor constrictor component of the response of blood vessels to 5-HT. 5-HT2A receptor antagonists have, therefore, been proposed as potential protectants against the effects of cerebral ischaemia. The aim of this study was to evaluate the effects of two relatively selective 5-HT2A receptor antagonists, ketanserin and ritanserin, on delayed hyperactivity and the ensuing neuronal degeneration induced by 3 minutes of bilateral carotid artery ligation in Mongolian gerbils. Effects were compared to that of flunarizine, which blocks calcium overload and served as a positive control in this paradigm. Temporal and/or rectal temperatures were measured and strictly controlled during the ischaemia and the early reperfusion phase. Locomotor activity was measured one day after the ischaemia and neuronal degeneration quantified 7 days later using an image analysis system (Quantimet 570, Leica). Global ischaemia in gerbils elicits hyperactivity associated with a delayed neuronal degeneration predominantly in the CA1 zone of the hippocampus. Ketanserin and ritanserin (3 and 10 mg/kg ip, twice daily for 3 days, pre- and postischaemia) did not protect the CA1 neurons against ischaemic damage. The postischaemic hyperactivity was inhibited only with the higher dose of ketanserin. As previously reported, flunarizine (30 mg/kg po) markedly reduced neuronal degeneration (-44.2%, p < 0.01) and totally abolished the ischaemia-induced hyperactivity. These data demonstrate that ketanserin and ritanserin are not effective protectants of the gerbil hippocampus against ischaemic damage when the body temperature of the animals is controlled, thus suggesting that 5-HT2A receptors are not directly implicated in the pathogenesis of global cerebral ischaemia in this model.

Neuroprotective Properties of the Novel Antiepileptic Lamotrigine in a Gerbil Model of Global Cerebral Ischemia

Elevated glutamate levels are thought to be a primary cause of neuronal death after global cerebral ischemia. The purpose of this study was to investigate the potential neuroprotective effects of lamotrigine, a novel antiepileptic drug that inhibits the release of glutamate in vitro, with both behavioral and histological measures of global ischemia in gerbils. The common carotid arteries of gerbils were occluded for either 5, 10, or 15 minutes. Twenty-one days after reperfusion, gerbils were tested for impairments in a spatial memory task (Morris water maze). After water maze testing the animals were killed, and damage to hippocampal pyramidal cells was assessed. The effect of lamotrigine on the behavioral and histological outcome of either 5 or 15 minutes of global ischemia was evaluated. Bilateral occlusion of the common carotid arteries for 5 minutes resulted in severe degeneration of hippocampal CA1 and CA2 pyramidal cells. Lamotrigine significantly prevented loss of hippocampal CA1 neurons when administered acutely (100 mg/kg PO) immediately after reperfusion or when administered in two equal doses of 30 or 50 mg/kg 2 hours before and immediately after reperfusion. Gerbils subjected to 5 minutes of ischemic insult were not impaired in their ability to solve a spatial memory task 21 days after cerebral ischemia. However, gerbils subjected to 10 and 15 minutes of carotid artery occlusion showed significant impairment in their ability to solve a water maze task. Lamotrigine significantly protected against the cognitive deficits associated with 15 minutes of cerebral ischemia. Histologically, increased durations of cerebral ischemia resulted in a progressive loss of CA1, CA2, and CA3 pyramidal cells. Lamotrigine completely protected gerbils exposed to 15 minutes of cerebral ischemia against CA3 cell loss and greatly reduced damage to the CA1 and CA2 cell tracts of the hippocampus. Lamotrigine also reduced the mortality associated with 15 minutes of ischemia. Lamotrigine had neuroprotective effects in a gerbil model of global cerebral ischemia. Lamotrigine protected gerbils against behavioral deficits resulting from 15 minutes of carotid occlusion and also prevented histological damage resulting from 5 and 15 minutes of global cerebral ischemia.

Neuroprotective activity of HU-211, a novel NMDA antagonist, in global ischemia in gerbils.

HU-211, a nonpsychotropic cannabinoid and a noncompetitive NMDA antagonist, was tested in a global ischemia model in the Mongolian gerbil. Male Mongolian gerbils underwent a 10-min bilateral common carotid artery occlusion. HU-211, administered i.v. at 4 mg/kg, 30 min postischemia, induced statistically significant neuroprotection of the CA1 subfield of the hippocampus. A dose-response study demonstrated an inverted U curve in which the 4 mg/kg dose induced the best neuroprotection in the CA1 subfield of the hippocampus (p < 0.05 ANOVA followed by Duncan's post-hoc test). The therapeutic window was then investigated, and in another study, HU-211 4 mg/kg were administered i.v. at 30, 60, 120, and 180 min postinsult. A statistically significant neuroprotection was detected at 30 and 60 min administration postinsult.

Anti-ischemia activity of HU-211, a non-psychotropic synthetic cannabinoid.

The novel tricyclic-terpenoid type cannabinoid, HU-211, was tested in gerbils and rats for protection against the effects of cerebral ischemia. Our transient ischemic models in gerbils and rats are based on the protection afforded against the lethal effects of global ischemia. HU-211 gave over 30% protection, by i.v. administration. The optimal dose ranges of HU-211 were between 5 and 10 mg/kg i.v. In gerbils we used a transient ischemia model induced by occlusion (10 min) of the bilateral common carotid arteries (BCCA). HU-211, 8 mg/kg i.v., gave a significantly (p < or = 0.05) better in vivo performed than a control group over three days following ischemia. Histology performed in gerbil model also resulted in significantly (p < 0.001) diminished degeneration area of CA1 in the hippocampus after treatment of HU-211. In the rat model, after four vessel occlusion (4VO) (20 min), HU-211 treatment significantly (p < 0.01) improved neurobehavior scoring. These results show that the new synthetic cannabinoid can protect against hippocampal neuron damage due to selective brain injury induced by cerebral global ischemia in gerbils or rats.

Polyamines can protect against ischemia-induced nerve cell death in gerbil forebrain

We have previously demonstrated that administration of the polyamines putrescine, spermidine, or spermine can prevent neuronal degeneration in rats during naturally occurring cell death or after injurious treatments such as nerve injury or monosodium glutamate neurotoxicity. The present study demonstrates that also in adult gerbils polyamine treatment can protect forebrain neurons from degeneration after ischemia. Neurons in the hippocampus and striatum were rescued from delayed cell death after brief (5 min) global ischemia in gerbils which were treated with daily injections (10 mg/kg) of polyamines. The evidence accrued, so far, indicates that systemic polyamines can protect a wide variety of central and peripheral neurons from natural or induced degeneration.