The selective 5-HT6 receptor antagonist SLV has putative cognitive- and social interaction enhancing properties in rodent models of cognitive impairment.

In the present study, our aim was to investigate whether the novel highly selective 5-hydroxytryptamine6 (5-HT6) receptor antagonist SLV can ameliorate impairments in cognition and social interaction with potential relevance for both schizophrenia and Alzheimer's disease (AD). SLV sub-chronically - treated Wistar rats reared in isolation showed significantly enhanced prepulse inhibition (PPI) and object recognition performance when compared to vehicle - treated rats. In the isolated rats, also a significant reduction in expression of hippocampal neural cell adhesion molecule polysialylation (NCAM-PSA) was found which was ameliorated following treatment with SLV (30mg/kg). The social engagement deficit in rats exposed in utero (on gestational day 12.5) to valproic acid (VPA) was reversed by treatment with SLV (30mg/kg). SLV (20 and 30mg/kg, p.o.) fully reversed MK-801 - induced deficits in the ORT and also scopolamine - induced deficits in both the Object Recognition Task (ORT) and Object Location Task (OLT) in Wistar rats. In addition, a combination of sub-optimal doses of SLV and donepezil attenuated scopolamine-induced ORT deficits. Furthermore, SLV (10mg/kg, p.o.) reversed spontaneous alternation deficits in the T-maze induced by MK-801 administration in Swiss mice and in aged C57Bl/6J mice. SLV additionally improved T-Maze spatial learning and passive avoidance learning in Sprague-Dawley rats with amyoid-beta (Aß) injections into the hippocampus. In contrast, no benefits were found with SLV or the tested reference compounds (donepezil and RVT-101) on cognitive performance of 12months old Tg2576 mice. Also, in the social recognition task, an absence of cognitive enhancing properties was observed with SLV on "normal forgetting" in Wistar rats. Finally, analysis of spontaneous inhibitory postsynaptic currents (sIPSCs) frequency recorded from pyramidal cells revealed a reduction in the presence of 1µM of SLV. In conclusion, SLV was investigated in several rodent animal models and found to be effective at a least effective dose (LED) of 20mg/kg and 10mg/kg (p.o.) in the rat and the mouse, respectively.

Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats.

The 5-hydroxytryptamine(6) (5-HT(6)) receptor has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the novel, selective 5-HT(6) antagonists compound (CMP) X and CMP Y and the reference 5-HT(6) antagonist GSK-742457 could ameliorate impairments in episodic memory in 3-months-old male Wistar rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer's disease, AD) was used as a positive reference compound. First, effects of the 5-HT(6) antagonists CMP X, CMP Y and GSK-742457 were investigated on object recognition task (ORT) performance in rats treated with the muscarinic antagonist scopolamine (0.1mg/kg, administered intraperitoneally, i.p., 30 min before trial 1). Second, effects of the combination of suboptimal doses of 5-HT(6) antagonists CMP X and CMP Y with the AChEI donepezil were studied, to determine whether the 5-HT(6) antagonists show additive synergism with donepezil in the ORT. Finally, effects of CMP Y, GSK-742457 and donepezil were investigated on object location task (OLT) performance in rats treated with scopolamine. Donepezil (1mg/kg, oral administration, p.o.), GSK-742457 (3mg/kg, i.p.), CMP X (3mg/kg, i.p.) and CMP Y (30 mg/kg, p.o.), all ameliorated the scopolamine-induced deficits in object recognition. In the ORT, we have found that combined administration of subthreshold doses of CMP X (1mg/kg, i.p.) and CMP Y (10mg/kg, p.o.) with the AChEI donepezil (0.1mg/kg, p.o.), enhanced memory performance in Wistar rats with deficits induced by scopolamine. Donepezil (0.1mg/kg, p.o.) alone had no discernable effects on performance. This suggests additive synergistic effects of the 5-HT(6) antagonists (CMP X and CMP Y) with donepezil on cognitive impairment. Finally, donepezil (1mg/kg, p.o.), GSK-742457 (10mg/kg, p.o.) and CMP Y (30 mg/kg, p.o.) also reduced scopolamine-induced deficits in the OLT. In conclusion, the 5-HT(6) antagonists were found to clearly improve episodic memory deficits induced by scopolamine. In addition, co-administration of the 5-HT(6) receptor antagonists CMP X and CMP Y with the AChEI donepezil to cognitively impaired rats also resulted in potentially additive enhancing effects on cognition. This suggests that these compounds could have potential as monotherapy, but also as adjunctive therapy in patients with AD treated with common treatments such as donepezil.

The classic lacunar syndromes: clinical and neuroimaging correlates.

BACKGROUND: Although lacunar syndromes (LSs) are aimed to be linked to lacunar infarcts, the relation between both is still not very well defined. PURPOSE: The present retrospective study tries to define more specifically the clinical and the neuroimaging characteristics of the five most classic LSs. PATIENTS AND METHODS: Out of a series of 1617 consecutive stroke patients, admitted to the Ghent University Hospital, 293 presented a classic LS. Magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) was performed within 5 days after stroke onset in 227 patients. An acute territorial infarct was demonstrated in 54 patients. The study population finally consisted of 173 patients with a classic LS in whom the responsible lacune was demonstrated or in the absence of another type of infarct. RESULTS: The responsible lacune was demonstrated with DWI in 104 patients. Pure motor stroke (MS) correlated significantly with the presence of the responsible lacune in the internal capsule (P = 0.000147) and with the stroke severity (P = 0.00724). No significant correlation was observed between the location of the lacunes and the other LS's. CONCLUSION: Pure MS has to be considered as the most specific lacunar syndrome.

The cortical involvement of territorial infarcts as a risk factor for stroke-related seizures.

BACKGROUND: The cortical involvement of territorial infarcts is considered to be a significant risk factor for the development of early- as well as late-onset seizures. However, it is not known which cortical regions are more susceptible to the development of stroke-related seizures. PATIENTS AND METHODS: In this retrospective study of 687 patients with territorial infarcts, 184 with stroke-related seizures were compared to 503 without seizures. The extent and the location of the infarcts were determined by computed tomography (CT) scans and/or magnetic resonance imaging (MRI) scans of the brain. The infarcts of the seizure and the non-seizure group were compared on digital cerebral vascular maps by superimposing the CT and/or MRI slices. RESULTS: In patients with late-onset seizures, the infarcts were significantly more frequent in the temporal and parietal branches of the middle cerebral artery in comparison to the non-seizure group. In patients with early-onset seizures and in those with seizures due to a recurrent stroke, the territory of the temporal and occipital branches of the middle cerebral artery was the predilection side of the infarcts. Generalized tonic-clonic seizures occurred mainly in cases of infarction in the deep territory of the middle cerebral and of the anterior choroidal artery. Status epilepticus was significantly correlated with infarcts in the posterior temporal region. CONCLUSION: Some infarct regions are the sides of predilection for stroke-related seizures according to their type and their onset-time.

Exposure to novelty and forced swimming evoke stressor-dependent changes in extracellular GABA in the rat hippocampus.

In the hippocampus, a brain structure critically important in the stress response, GABA controls neuronal activity not only via synaptic inhibition, but also via tonic inhibition through stimulation of extrasynaptic GABA receptors. The extracellular level of GABA may represent a major determinant for tonic inhibition and, therefore, it is surprising that its responsiveness to stress has hardly been investigated. To clarify whether hippocampal extracellular GABA levels change in response to acute stress, we conducted an in vivo microdialysis study in rats. We found that dialysate GABA levels respond to various neuropharmacological manipulations such as reuptake inhibition, elevated concentrations of K(+), tetrodotoxin and baclofen, indicating that a large proportion of hippocampal extracellular GABA depends on neuronal release and that GABA re-uptake plays a role in determining the extracellular levels of this neurotransmitter. Next, rats were exposed to a novel cage or to forced swimming in 25 degrees C water. Interestingly, these two stressors resulted in opposite effects. Novelty caused a fast increase in GABA (120% of baseline), whereas forced swimming resulted in a profound decrease (70% of baseline). To discriminate between the psychological and physical aspects (i.e. the effects on body temperature) of forced swimming, another group of animals was forced to swim at 35 degrees C. This stressor, like novelty, caused an increase in hippocampal GABA, suggesting a stimulatory effect of psychological stress. The effects of novelty could not be blocked by the corticotropin-releasing factor receptor antagonist D-Phe-CRF(12-41). These results are the first to demonstrate stressor-dependent changes in hippocampal extracellular GABA; an observation which may be of particular significance for GABAergic tonic inhibition of hippocampal neurons.

Immunocytochemical demonstration of developmental distribution of muscarinic acetylcholine receptors in rat parietal cortex.

The present investigation reveals many cortical neurons immunopositive for M35, the monoclonal antibody raised against purified muscarinic acetylcholine receptor (mAChR) proteins, in the early postnatal rat brain. The ontogeny of mAChR expression, exemplified on the parietal neocortex, was studied in a series of rat pups from postnatal days (PD) 1, 3, 7, 14 and 21. Immunoprecipitation in the parietal somatosensory cortex was manifest in the population of pyramidal neurons during postnatal development. In particular during the early postnatal ages, until 2 weeks after birth, M35 immunoreactivity (M35-ir) was present in all neuronal compartments, indicating transportation of mAChR protein in axonal and dendritic processes as observed in light and electron microscopic analysis. The immunoprecipitation in the apical dendrites yielded dense labeling in layer 1 where the distal processes of the pyramidal dendrites branched extensively forming a plexus that intermingled with horizontal fibers in this superficial layer. At PD21, immunolabeling in layer 1 and in axons of pyramidal cells was reduced compared to earlier ages suggesting a transient expression of mAChRs in these neuronal structures. The development of M35-ir in the cortex appeared to antedate that of its cholinergic afferentation as indicated by AChE histochemical study.

The ultradian and circadian rhythms of free corticosterone in the brain are not affected by gender: an in vivo microdialysis study in Wistar rats.

Recently, we described that free corticosterone levels in the brain of male Wistar rats, as assessed by in vivo microdialysis, show an ultradian rhythm with a pulse frequency of 1.2 pulses/h. To establish whether gender influences brain free corticosterone rhythms, we studied free corticosterone levels in the female Wistar rat under baseline and stressful conditions using microdialysis in the hippocampus. Analysis of the data with the PULSAR algorithm revealed that hippocampal free corticosterone levels show a clear ultradian pattern in female rats with a pulse frequency of 1.16+/-0.05 pulses/h between 09.00 h and 21.00 h. Further analysis showed that the pulse amplitude is significantly higher during the late afternoon/early night (15.00-21.00 h) than during the morning/early afternoon (09.00-15.00 h) phase (0.13+/-0.03 versus 0.07+/-0.01 microg/dl, respectively, P < 0.05). Pulse characteristics were extremely reproducible as demonstrated by the almost identical pulse parameters derived from two consecutive 24-h periods [pulse frequency: 1.13+/-0.09 and 1.19+/-0.08 pulses/h; pulse amplitude: 0.11+/-0.05 and 0.10+/-0.02 microg/dl for day 1 and day 2 (09.00-21.00 h) respectively, P > 0.05]. Both exposure to a novel environment and forced swim stress increased hippocampal free corticosterone levels. However, the stress-induced rise reached higher levels and was more prolonged after forced swimming (area under the curve: 46.84+/-9.25 and 12.08+/-1.69 arbitrary units for forced swimming and novelty stress respectively, P = 0.01). Importantly, the ultradian rhythm was rapidly restored after termination of the stress response. This is the first demonstration that the female rat brain is exposed to free corticosterone levels that follow a circadian as well as an ultradian pattern and show almost identical pulse characteristics as recently reported in male animals. These observations are of significance for further investigations into the dynamics of glucocorticoid action in the brain of both genders.

Delayed transient worsening of neurological deficits after ischaemic stroke.

BACKGROUND: Although the causes of stroke recurrence are well known, no particular study deals with the specific issue of late-onset transient worsening of the neurological deficit (TWND) after an ischaemic stroke. PATIENTS AND METHODS: In this retrospective study the aetiology of the TWNDs in 101 patients was compared to the causes of transient ischaemic attacks (TIAs) in 115 patients. All patients had a full cardiovascular and neuroimaging examination according to current guidelines. An electroencephalogram (EEG) was performed when necessary. The diagnosis of inhibitory seizures was retained when the EEG showed periodic lateralized epileptiform discharges or intermittent rhythmic delta activities, or when the patient developed typical seizures afterwards. RESULTS: Arterial hypertension and diabetes were more prevalent vascular risk factors in TWND patients. Small-vessel disease and inhibitory seizures were a more frequent cause of TWNDs than of TIAs. Extracranial large-vessel disease predominates in TIA patients. The global prevalence of cardiac diseases as cause of TIAs and TWNDs was the same, although severe ulcerous plaques of the aortic arch and patent foramen ovale with atrial septum aneurysm occurred more frequently in TWND patients. CONCLUSIONS: The most frequent causes of late-onset TWNDs were different from those of TIAs. Apart from repeated neuroimaging of the brain, exhaustive cardiac investigations and EEG are mandatory in TWND patients.