Transformation of diffuse beta-amyloid precursor protein and beta-amyloid deposits to plaques in the thalamus after transient occlusion of the middle cerebral artery in rats.

BACKGROUND AND PURPOSE: The present study examined the long-term presence of beta-amyloid precursor protein (APP) and beta-amyloid (Abeta) accumulation in the rat thalamus after focal cerebral ischemia. METHODS: Male Wistar rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 hours. Sensorimotor outcome was assessed using a tapered/ledged beam-walking task after operation. The distribution of APP and Abeta was examined immunohistochemically at 1 week, 1 month, and 9 months after MCAO. RESULTS: MCAO caused a long-lasting deficit in forelimb and hind limb function assessed using the beam-walking test. Histologic examination revealed a transient increase in APP and Abeta staining in axons in the corpus callosum and in neurons at the border of the ischemic region. APP and Abeta deposits persisted in the thalamic nuclei (ventroposterior lateral and ventroposterior medial nuclei), eventually leading to dense plaque-like deposits by the end of the 9-month follow-up. The deposits were surrounded by an astroglial scar. The deposits were positive for Abeta and N-terminal APP, but not for C-terminal APP. Antibodies against the C-terminal of Abeta, ie, Abeta42 and Abeta40, showed a preferential staining for Abeta42. Congo red or thioflavine S did not stain the deposits. CONCLUSIONS: The present results demonstrated the persistent presence and aggregation of APP and Abeta, or their fragments, to dense plaque-like deposits in the ventroposterior lateral and ventroposterior medial nuclei of rats subjected to focal cerebral ischemia.

Behavioral effects of photothrombotic ischemic cortical injury in aged rats treated with the sedative-hypnotic GABAergic drug zopiclone.

Sedative-hypnotic drugs commonly used in the elderly may affect functional recovery following cerebrovascular events. Previous research has shown that prolonged exposure to diazepam can interfere with recovery of function and exaggerate tissue loss after brain injury. The present study evaluated the effect of zopiclone, a widely used hypnotic drug, on functional and histological outcome after cortical photothrombosis in aged rats, which might be particularly vulnerable to brain insults and inhibitory sedative-hypnotic drugs. Aged Wistar rats were treated with zopiclone at a dose of 3 mg/kg (i.p., once a day) beginning 4 days before ischemia induction and continuing for 23 days. Sensorimotor recovery was assessed by a new ledged beam-walking test and spatial learning by the Morris water-maze. After a 7-day washout period all rats were administered a single dose of zopiclone (3 mg/kg, i.p.) and retested. Infarct volumes were measured from nitroblue tetrazolium-stained sections at the end of the experiment. Beam-walking data showed that ischemic rats treated with zopiclone were not more impaired than untreated rats. Indeed, they showed fewer faults with the impaired hindlimb than ischemic controls on post-operative day 16. Water-maze performance was not affected by zopiclone. After the washout period a single dose of zopiclone did not worsen forelimb or hindlimb function, but seemed to improve performance in the water-maze test. Cortical infarct volumes were similar in ischemic controls and ischemic rats treated with zopiclone. In conclusion, zopiclone was not detrimental and even seemed to improve behavioral outcome without affecting ischemic damage in aged rats subjected to cortical photothrombosis.

Behavioral and histological effects of chronic antipsychotic and antidepressant drug treatment in aged rats with focal ischemic brain injury.

Psychotropic drugs are commonly used in the elderly, including those who may sustain ischemic attacks. Concomitant CNS medication may interfere with functional recovery. The present study evaluated the effect of risperidone, an atypical neuroleptic, and fluoxetine, a selective serotonin reuptake inhibitor, on histological and functional outcome after experimental stroke in aged rats, which might be more vulnerable to brain insults. Aged Wistar rats were treated with risperidone at a dose of 1 mg/kg (i.p., once a day), fluoxetine at a dose of 5 mg/kg (i.p., once a day), or their combination. Drug treatment was started 7 days before focal cortical photothrombosis (Rose Bengal, 20 mg/kg) and continued for 28 days thereafter. Sensorimotor recovery was assessed by a new beam-walking test and spatial learning by the Morris water-maze before cortical stroke, immediately after stroke, and at the end of follow-up. Infarct volumes were measured from nitroblue tetrazolium-stained sections at the end of follow-up. The high slip ratio for the contralateral hindlimb in ischemic rats treated with risperidone indicated sensorimotor impairment when tested 2 h after drug administration. Sensorimotor impairment was not observed, however, when the rats were tested 24 h after risperidone administration. Similarly, water-maze performance was impaired 2 h after risperidone. Fluoxetine did not affect sensorimotor or water-maze performance. Cortical infarct volumes were not different in ischemic controls and ischemic rats treated with antipsychotic drugs. The present study showed that an atypical neuroleptic, risperidone, acutely impairs behavioral performance, but does not affect histological or functional outcome in aged rats subjected to cortical photothrombosis.

Effect of cholinergic medication, before and after focal photothrombotic ischemic cortical injury, on histological and functional outcome in aged and young adult rats.

The present study evaluated the effect of galanthamine, a selective competitive cholinesterase inhibitor, on histological and functional outcome after experimental stroke in rats. Cholinesterase inhibitors are commonly used as cognitive enhancers for dementia in aged people, including those who may sustain ischemic attacks. Young adult (5 months) and aged (24 months) rats were treated with saline or galanthamine at a dose of 2.5 mg/kg (i.p., once a day). Drug treatment started 4 days before focal cortical photothrombosis (Rose Bengal, 20 mg/kg) and continued for 21 days thereafter. Sensorimotor recovery was assessed by a new beam-walking test and spatial learning by the Morris water-maze over a 3-week follow-up period. Infarct volumes were measured from nitroblue tetrazolium-stained sections at the end of follow-up. Infarct volumes in the cortex were similar in ischemic controls and ischemic rats treated with galanthamine. In the beam-walking test, there was a transient impairment forelimb function and a permanent impairment in hindlimb after cortical infarct both in young adult and aged rats. Galanthamine treatment did not affect the sensorimotor recovery rate. Analysis of water-maze data did not reveal significant differences in length of path, escape latency, or swim speed between sham-operated, ischemic controls and ischemic rats treated with galanthamine. In conclusion, present findings suggest that the aging brain has considerable plastic capacity to maintain functioning after focal cerebral insults restricted to the motor cortex. Galanthamine is not beneficial with respect to the histological or functional outcome in rats subjected to cortical photothrombosis.

Influence of enriched environment on spatial learning following cerebral insult.

The fact that our brain is continuously shaped by the environment and experience presents many challenges. It was noted several decades ago that exposure of a laboratory rat to a complex environment alters its brain and improves problem solving in complex tasks. Rats that are housed in an enriched environment can better compensate for brain lesion-induced deficits and resist neurodegeneration. In this article, the role of an enriched environment on brain plasticity following experimentally-induced lesions is discussed.

Effects-of fluoxetine on sensorimotor and spatial learning deficits following focal cerebral ischemia in rats.

Purpose: The present study investigated the effects of fluoxetine, a serotonin reuptake blocker, on behavioral deficits of rats subjected to transient focal cerebral ischemia. Methods: The right middle cerebral artery of rats was occluded for 120 min using the intraluminal filament method. Fluoxetine treatment (5 mg/kg, i.p.) was started 2 days after ischemia induction and treatment was continued for 10 days thereafter. Sensorimotor recovery was assessed using the limb-placing test and cognitive impairment was assessed using a water-maze test at the end of the experiment. Results: Fluoxetine treatment did not improve performance of ischemic rats in the limb-placing test. Nor was the ischemia-induced deficit in the water-maze test affected by fluoxetine. The infarct volumes in the cortex or striatum, determined after the experiment, were not different between ischemic groups. Conclusion: These results suggest that subchronic fluoxetine treatment following experimental focal cerebral ischemia is not detrimental to behavioral outcome, but it also does not enhance spontaneous sensorimotor recovery or attenuate spatial learning deficits.