Frank Block

Spatial learning is affected by transient occlusion of common carotid arteries (2VO) : comparison of behavioural and histopathological changes after 2VO and four-vessel-occlusion in rats

Place learning in the Morris water maze following transient (24 min) occlusion of the common carotid arteries (2VO), and following permanent occlusion of both vertebral arteries plus transient (20 min) clamping of the carotids (4VO) was investigated in rats 6-9 days after occlusion. Both 2VO and 4VO treatment increased the latency to find the hidden platform during escape trials; spatial bias, tested in a probe trial, was decreased. Histological analysis revealed neural necrosis in the CA1 sector of the hippocampus in 4VO rats but not in 2VO animals. The data suggest that an experimentally induced reduction in cerebral blood flow of 50% (after 2VO) or 95% (after 4VO) produces persistent functional changes even in absence of actual neural damage.

Different Mechanisms of Secondary Neuronal Damage in Thalamic Nuclei After Focal Cerebral Ischemia in Rats

Background and Purpose— After focal cerebral ischemia, depending on its localization and extent, secondary neuronal damage may occur that is remote from the initial lesion. In this study differences in secondary damage of the ventroposterior thalamic nucleus (VPN) and the reticular thalamic nucleus (RTN) were investigated with the use of different ischemia models. Methods— Transient middle cerebral artery occlusion (MCAO) leads to cortical infarction, including parts of the basal ganglia such as the globus pallidus, and to widespread edema. Photothrombotic ischemia generates pure cortical infarcts sparing the basal ganglia and with only minor edema. Neuronal degeneration was quantified within the ipsilateral RTN and VPN 14 days after ischemia. Glial reactions were studied with the use of immunohistochemistry. Results— MCAO resulted in delayed neuronal cell loss of the ipsilateral VPN and RTN. Glial activation occurred in both nuclei beginning after 24 hours. Photothrombotic ischemia resulted in delayed neuronal cell loss only within the VPN. Even 2 weeks after photothrombotic ischemia, glial activation could only be seen within the VPN. Conclusions— Pure cortical infarcts after photothrombotic ischemia, without major edema and without effects on the globus pallidus of the basal ganglia, only lead to secondary VPN damage that is possibly due to retrograde degeneration. MCAO, which results in infarction of cortex and globus pallidus and which causes widespread edema, leads to secondary damage in the VPN and RTN. Thus, additional RTN damage may be due to loss of protective GABAergic input from the globus pallidus to the RTN or due to the extensive edema. Retrograde degeneration is not possible because the RTN, in contrast to the VPN, has no efferents to the cortex.

Recovery From Aphasia After Hemicraniectomy for Infarction of the Speech-Dominant Hemisphere

Background and Purpose— The space-occupying effect of cerebral edema limits survival chances of patients with severe ischemic stroke. Besides conventional therapies to reduce intracranial pressure, hemicraniectomy can be considered as a therapeutic option after space-occupying cerebral infarction. There is controversy regarding the use of this method in patients with infarction of the speech-dominant hemisphere. Methods— In 14 patients with infarction of the dominant hemisphere and subsequent treatment with hemicraniectomy, recovery from aphasic symptoms was evaluated retrospectively. A group of patients who were treated between 1994 and 2003 in our aphasia ward was selected for the study. In all patients, a psychometric quantification was accomplished applying the Aachen Aphasia Test at least twice within a mean observation period of 470 days. Results— A significant improvement of the statistical parameters representing different aspects of aphasia was observed in 13 of 14 patients. Also, an increase of the ability to communicate was evident in 13 patients. Young age at the time of stroke and early poststroke decompressive surgery were identified as main predictors for recovery from aphasia. Conclusions— A significant improvement of aphasic symptoms can be observed in a preselected group of patients after a massive stroke of the speech-dominant hemisphere treated by consecutive hemicraniectomy. Therefore, decompressive surgery can be considered for the treatment of this kind of stroke.

Memantine reduces functional and morphological consequences induced by global ischemia in rats

In this study the effect of memantine, an antagonist at the N-methyl-D-aspartate receptor, on spatial learning deficit and on neuronal damage following transient cerebral ischemia was evaluated. Global ischemia was induced by four-vessel-occlusion (4VO) for 20 min in rats. Memantine was administered 20 min before induction of ischemia at a dose of 10 or 20 mg/kg. One week after surgery spatial learning was tested in the Morris water maze. Treatment with the higher dose of memantine reduced the increase in escape latency and in swim distance induced by 4VO. Neuronal damage in the CA1 sector of the hippocampus and in the striatum produced by 4VO was significantly attenuated by 20 mg/kg memantine. Treatment with the lower dose of memantine had no influence on the deficit in spatial learning and the neuronal damage resulting from ischemia. The present data demonstrate that treatment with a neuroprotective agent like memantine can reduce functional as well as morphological sequelae induced by ischemia.

Retinal ischemia induced by occlusion of both common carotid arteries in rats as demonstrated by electroretinography

In 2 models of reduced cerebral blood flow-permanent occlusion of the vertebral arteries plus transient occlusion of the common carotid arteries (4VO) and transient clamping of the common carotid arteries (BCCA)-the acute effects on the electrical function of the retina were monitored by recording the photopic electroretinogram. During both 4VO and BCCA the amplitude of the b-wave was reduced. Within 30 min of reperfusion after 4VO and after BCCA the b-wave had fully recovered. In contrast, the a-wave was not affected by either treatment. The data suggest that occlusion of common carotid arteries leads to retinal ischemia and might represent a useful model of amaurosis fugax.

Expression of IL-6 in the ischemic penumbra.

We examined the expression of IL-6 within the ischemic penumbra at various time points after transient (3 h) middle cerebral occlusion (MCA-O) in rats. The animals were killed at 1, 3, 7 or 14 days following operation. Coronal brain sections were processed for immunohistochemistry with antibodies against GFAP, OX 42, IL-6 and Nissl-staining. Glial activation within the penumbra started on day one after ischemia and persisted up to day 14. Expression of IL-6 was not present in sham-operated controls. One day after MCA-O there were several IL-6-positive cells in the penumbra. This expression of IL-6 increased on day 3 and remained elevated up to day 14. According to the shape of the IL-6-positive cells they seem to be microglia and neurons. The present results demonstrate a longlasting expression of IL-6 in the ischemic penumbra.

Remote microglial activation in the quinolinic acid model of Huntington's disease

Intrastriatal injection of quinolinic acid (QA) in the rat leads to several structural and biochemical events which resemble neuropathological changes seen in the striatum of Huntingtons disease patients. In the present experiment the accompanying microglial response in striatal projection areas following QA injection was studied immunocytochemically using monoclonal macrophage/microglial markers. After injection of 240 nmol of QA a marked microglial reaction was observed in the entire striatum, whereas injection of the same amount of solvent resulted only in a local microglial reaction around the injection site. Activated microglia were also found in the globus pallidus (GP), the entopeduncular nucleus (EP), the substantia nigra (SN), and the ventroanterior/ventrolateral, the ventromedial, and, in some rats, the reticular thalamic nucleus. The remote microglial reaction started in the first-order projection areas at Day 1 (GP) or Day 3 (EP, SN) and was found in the second-order projection areas (thalamic nuclei) by Day 5. Areas projecting to the striatum such as the amygdala and intralaminar thalamic nuclei remained free of activated microglia. It is concluded that a microglial response in striatal projection areas accompanies excitotoxic striatal injury. Anterograde degeneration of striatal projection neurons can explain the microglial activation in first-order projection areas but other mechanisms such as neuronal hyperexcitation following removal of inhibitory striatal input must be responsible for the rapid transsynaptic microglial activation seen in the thalamus.

N-methyl-D-aspartate (NMDA)-mediated muscle relaxant action of flupirtine in rats.

The present study examined in urethane-chloralose anaesthetized rats whether N-methyl-D-aspartate (NMDA) is involved in the depressant effect of flupirtine on the monosynaptic Hoffmann (H)-reflex recorded from plantar foot muscles and on polysynaptic flexor reflexes recorded from tibialis muscle. Intrathecal administration of both the specific NMDA antagonist (-)-2-amino-7-phosphonoheptanoate and of flupirtine depressed the polysynaptic flexor reflex without affecting the monosynaptic H-reflex. In contrast, the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione depressed the H-reflex without affecting the flexor reflex. The depressant effect of flupirtine on the flexor reflex was prevented by co-administration of NMDA, but not by co-administration of the non-NMDA agonist alpha-amino-3-hydroxy-5-tertbutyl-4-isoxazolepropionic acid. These observations suggest that NMDA might be involved in the action of flupirtine.

Rolipram reduces excitotoxic neuronal damage.

Proinflammatory cytokines are supposed to be involved in the pathophysiology of neuronal damage following excitotoxic lesions. We examined the effect of rolipram, a TNF-α-inhibitor, on excitotoxic neuronal damage. Quinolinic acid (240 nmol in 1 μl) was injected stereotactically into the striatum of male Wistar rats. Four groups of QA rats were treated i.p. with solvent, MK-801 (4 mg/kg) or rolipram (0.3 mg/kg) which was started either 6 or 24 h after QA injection and continued with daily applications for 14 days. QA injection induced neuronal damage which affected 93% of the striatal area. MK-801 reduced this damage to 12% of the striatal area. Treatment with rolipram when started at 6 h after QA injection resulted in neuronal damage amounting to 60%; the result after starting at 24 h was not different from solvent (91%). The present results demonstrate that rolipram reduces neuronal damage induced by intrastriatal QA application.

S-emopamil ameliorates ischemic brain damage in rats : histological and behavioural approaches

Transient ischemia induced by 4 vessel occlusion (4VO) in rats is known to produce neuronal damage to particular brain structures such as the CA1 sector of the hippocampus. Behavioural changes associated with ischemic lesioning of this brain region are an impairment in spatial learning of rats tested in a water maze (14). In the present study, it was investigated whether pretreatment with S-emopamil, a Ca2(+)-channel blocker as well as a 5-HT2 antagonist, prevents the occurrence of hippocampal cell damage and/or spatial learning impairments in rats subjected to 4VO. Neuronal lesioning in the hippocampus was significantly reduced following pretreatment with S-emopamil in 4VO rats. In addition, S-emopamil treated animals showed an improved spatial learning ability compared to saline treated 4VO rats. It is suggested that S-emopamil may exert a protective effect under ischemic conditions. The possible mechanisms involved are discussed.