Striatal Blood Flow Research Articles

Striatal Blood Flow Changes by Middle Cerebral Artery Occlusion and Its Effect on Neurological Deficits in Mice.

We attempted to record the regional cerebral blood flow (CBF) simultaneously at various regions of the cerebral cortex and the striatum during middle cerebral artery (MCA) occlusion and to evaluate neurological deficits and infarct formation. In male C57BL/6J mice, CBF was recorded in three regions including the ipsilateral cerebral cortex and the striatum with laser Doppler flowmeters, and the origin of MCA was occluded with a monofilament suture for 15-90 min. After 48 h, neurological deficits were evaluated, and infarct was examined by triphenyltetrazolium chloride (TTC) staining. CBF decrease in the striatum was approximately two-thirds of the MCA-dominant region of the cortex during MCA occlusion. The characteristic CBF fluctuation because of spontaneously occurred spreading depolarization observed throughout the cortex was not found in the striatum. Ischemic foci with slight lower staining to TTC were found in the ipsilateral striatum in MCA-occluded mice for longer than 30 min (n = 54). Twenty-nine among 64 MCA-occluded mice exhibited neurological deficits even in the absence of apparent infarct with minimum staining to TTC in the cortex, and the severity of neurological deficits was not correlated with the size of the cortical infarct. Neurological deficits might be associated with the ischemic striatum rather than with cortical infarction.

Chronic hypometabolism in striatum and hippocampal network after traumatic brain injury and their relation with memory impairment – [18F]-FDG-PET and MRI 4 months after fluid percussion injury in rat

Hippocampal and thalamo-cortico-striatal networks are critical for memory function as well as execution of a variety of learning strategies. In subjects with memory impairment as a sequel of traumatic brain injury (TBI), the contribution of late metabolic depression across these networks to memory deficit is poorly understood. We used [18F]-FDG-PET to measure chronic post-TBI glucose uptake in the striatum and connected brain areas (septal and temporal hippocampus, thalamus, entorhinal cortex, frontoparietal cortex and amygdala) in rats with lateral fluid-percussion injury (LFPI). Then we assessed a link between network hypometabolism and memory impairment. At 4 months post TBI, glucose uptake was decreased in ipsilateral striatum (10%, p = 0.027), frontoparietal cortex (17%, p = 0.00009), and hippocampus (22%, p = 0.027) as compared to sham operated controls. Thalamic uptake was 6% lower ipsilaterally than contralaterally, p = 0.00004). At 5 months, Morris water maze (MWM) showed memory impairment in 83% of the rats with TBI. The lower the hippocampal or striatal [18F]-FDG uptake, the poorer the MWM performance (hippocampus: r = −0.471, p < 0.05; striatum: r = −0.696, p < 0.001). Striatal [18F]-FDG-PET identified the injured animals with memory impairment with 100% specificity and sensitivity (AUC = 1.000, p = 0.009). Interestingly, the low striatal glucose uptake was a better diagnostic biomarker for memory impairment than the reduced hippocampal (AUC = 0.806, p = 0.112) or entorhinal (AUC = 0.528, p = 0.885) glucose uptake. The volumetric atrophy assessed in T2 weighted MRI or the gliotic area in Nissl staining did not correlate with glucose uptake. Arterial spin labeling did not indicate any reduction in the striatal blood flow. Our study suggests that TBI-induced chronic hypometabolism in striatum contributes to the cognitive deficits.

The Vasomotor Response to Dopamine Is Altered in the Rat Model of l-dopa-Induced Dyskinesia.

ABSTRACTBackgroundLevodopa (l‐dopa) is the frontline treatment for motor symptoms of Parkinson's disease. However, prolonged use of l‐dopa results in a motor complication known as levodopa‐induced dyskinesia (LID) in ~50% of patients over 5 years.ObjectivesWe investigated neurovascular abnormalities in a rat model of LID by examining changes in angiogenesis and dopamine‐dependent vessel diameter changes.MethodsDifferences in striatal and nigral angiogenesis in a parkinsonian rat model (6‐OHDA lesion) treated with 2 doses of l‐dopa (saline, 2, and 10 mg/kg/day subcutaneous l‐dopa treatment for 22 days) by 5‐bromo‐2'‐deoxyuridine (BrdU)‐RECA1 co‐immunofluorescence. Difference in the vasomotor response to dopamine was examined with 2‐photon laser scanning microscopy and Dodt gradient imaging.ResultsWe found that the 10 mg/kg l‐dopa dosing regimen induced LID in all animals (n = 5) and induced significant angiogenesis in the striatum and substantia nigra. In contrast, the 2 mg/kg treatment induced LID in 6 out of 12 rats and led to linearly increasing LID severity over the 22‐day treatment period, making this a promising model for studying LID progression longitudinally. However, no significantly different level of angiogenesis was observed between LID versus non‐LID animals. Dopamine‐induced vasodilatory responses were exaggerated only in rats that show LID‐like signs compared to the rest of groups. Additionally, in juvenile rats, we showed that DA‐induced vasodilation is preceded by increased Ca2+ release in the adjacent astrocytes.ConclusionThis finding supports that astrocytic dopamine signaling controls striatal blood flow bidirectionally, and the balance is altered in LID. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Transcranial contrast-enhanced ultrasound in the rat brain reveals substantial hyperperfusion acutely post-stroke

Direct and real-time assessment of cerebral hemodynamics is key to improving our understanding of cerebral blood flow regulation in health and disease states such as stroke. While a number of sophisticated imaging platforms enable assessment of cerebral perfusion, most are limited either spatially or temporally. Here, we applied transcranial contrast-enhanced ultrasound (CEU) to measure cerebral perfusion in real-time through the intact rat skull before, during and after ischemic stroke, induced by intraluminal filament middle cerebral artery occlusion (MCAO). We demonstrate expected decreases in cortical and striatal blood volume, flow velocity and perfusion during MCAO. After filament retraction, blood volume and perfusion increased two-fold above baseline, indicative of acute hyperperfusion. Adjacent brain regions to the ischemic area and the contralateral hemisphere had increased blood volume during MCAO. We assessed our data using wavelet analysis to demonstrate striking vasomotion changes in the ischemic and contralateral cortices during MCAO and reperfusion. In conclusion, we demonstrate the application of CEU for real-time assessment of cerebral hemodynamics and show that the ischemic regions exhibit striking hyperemia post-MCAO. Whether this post-stoke hyperperfusion is sustained long-term and contributes to stroke severity is not known.

An investigation of regional cerebral blood flow and tissue structure changes after acute administration of antipsychotics in healthy male volunteers.

Chronic administration of antipsychotic drugs has been linked to structural brain changes observed in patients with schizophrenia. Recent MRI studies have shown rapid changes in regional brain volume following just a single dose of these drugs. However, it is not clear if these changes represent real volume changes or are artefacts ("apparent" volume changes) due to drug-induced physiological changes, such as increased cerebral blood flow (CBF). To address this, we examined the effects of a single, clinical dose of three commonly prescribed antipsychotics on quantitative measures of T1 and regional blood flow of the healthy human brain. Males (n = 42) were randomly assigned to one of two parallel groups in a double-blind, placebo-controlled, randomized, three-period cross-over study design. One group received a single oral dose of either 0.5 or 2 mg of risperidone or placebo during each visit. The other received olanzapine (7.5 mg), haloperidol (3 mg), or placebo. MR measures of quantitative T1, CBF, and T1-weighted images were acquired at the estimated peak plasma concentration of the drug. All three drugs caused localized increases in striatal blood flow, although drug and region specific effects were also apparent. In contrast, all assessments of T1 and brain volume remained stable across sessions, even in those areas experiencing large changes in CBF. This illustrates that a single clinically relevant oral dose of an antipsychotic has no detectable acute effect on T1 in healthy volunteers. We further provide a methodology for applying quantitative imaging methods to assess the acute effects of other compounds on structural MRI metrics. Hum Brain Mapp 39:319-331, 2018. © 2017 Wiley Periodicals, Inc.

Presynaptic Dopamine Synthesis Capacity in Schizophrenia and Striatal Blood Flow Change During Antipsychotic Treatment and Medication-Free Conditions.

Standard-of-care biological treatment of schizophrenia remains dependent upon antipsychotic medications, which demonstrate D2 receptor affinity and elicit variable, partial clinical responses via neural mechanisms that are not entirely understood. In the striatum, where D2 receptors are abundant, antipsychotic medications may affect neural function in studies of animals, healthy volunteers, and patients, yet the relevance of this to pharmacotherapeutic actions remains unresolved. In this same brain region, some individuals with schizophrenia may demonstrate phenotypes consistent with exaggerated dopaminergic signaling, including alterations in dopamine synthesis capacity; however, the hypothesis that dopamine system characteristics underlie variance in medication-induced regional blood flow changes has not been directly tested. We therefore studied a cohort of 30 individuals with schizophrenia using longitudinal, multi-session [15O]-water and [18F]-FDOPA positron emission tomography to determine striatal blood flow during active atypical antipsychotic medication treatment and after at least 3 weeks of placebo treatment, along with presynaptic dopamine synthesis capacity (ie, DOPA decarboxylase activity). Regional striatal blood flow was significantly higher during active treatment than during the placebo condition. Furthermore, medication-related increases in ventral striatal blood flow were associated with more robust amelioration of excited factor symptoms during active medication and with higher dopamine synthesis capacity. These data indicate that atypical medications enact measureable physiological alterations in limbic striatal circuitry that vary as a function of dopaminergic tone and may have relevance to aspects of therapeutic responses.

Effects of striatal nitric oxide production on regional cerebral blood flow and seizure development in rats exposed to extreme hyperoxia.

The endogenous vasodilator and signaling molecule nitric oxide has been implicated in cerebral hyperemia, sympathoexcitation, and seizures induced by hyperbaric oxygen (HBO2) at or above 3 atmospheres absolute (ATA). It is unknown whether these events in the onset of central nervous system oxygen toxicity originate within specific brain structures and whether blood flow is diverted to the brain from peripheral organs with high basal flow, such as the kidney. To explore these questions, total and regional cerebral blood flow (CBF) were measured in brain structures of the central autonomic network in anesthetized rats in HBO2 at 6 ATA. Electroencephalogram (EEG) recordings, cardiovascular hemodynamics, and renal blood flow (RBF) were also monitored. As expected, mean arterial blood pressure and total and regional CBF increased preceding EEG spikes while RBF was unaltered. Of the brain structures examined, the earliest rise in CBF occurred in the striatum, suggesting increased neuronal activation. Continuous unilateral or bilateral striatal infusion of the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester attenuated CBF responses in that structure, but global EEG discharges persisted and did not differ from controls. Our novel findings indicate that: 1) cerebral hyperemia in extreme HBO2 in rats does not occur at the expense of renal perfusion, highlighting the remarkable autoregulatory capability of the kidney, and 2) in spite of a sentinel increase in striatal blood flow, additional brain structure(s) likely govern the pathogenesis of HBO2-induced seizures because EEG discharge latency was unchanged by local blockade of striatal nitric oxide production and concomitant hyperemia.

Spontaneously hypertensive rats display reduced microglial activation in response to ischemic stroke and lipopolysaccharide

BackgroundFor successful translation to clinical stroke studies, the Stroke Therapy Academic Industry Round Table criteria have been proposed. Two important criteria are testing of therapeutic interventions in conscious animals and the presence of a co-morbidity factor. We chose to work with hypertensive rats since hypertension is an important modifiable risk factor for stroke and influences the clinical outcome. We aimed to compare the susceptibility to ischemia in hypertensive rats with those in normotensive controls in a rat model for induction of ischemic stroke in conscious animals.MethodsThe vasoconstrictor endothelin-1 was stereotactically applied in the vicinity of the middle cerebral artery of control Wistar Kyoto rats (WKYRs) and Spontaneously Hypertensive rats (SHRs) to induce a transient decrease in striatal blood flow, which was measured by the Laser Doppler technique. Infarct size was assessed histologically by Cresyl Violet staining. Sensory-motor functions were measured at several time points using the Neurological Deficit Score. Activation of microglia and astrocytes in the striatum and cortex was investigated by immunohistochemistry using antibodies against CD68/Iba-1 and glial fibrillary acidic protein.Results and conclusionsThe SHRs showed significantly larger infarct volumes and more pronounced sensory-motor deficits, compared to the WKYRs at 24 h after the insult. However, both differences disappeared between 24 and 72 h. In SHRs, microglia were less susceptible to activation by lipopolysaccharide and there was a reduced microglial activation after induction of ischemic stroke. These quantitative and qualitative differences may be relevant for studying the efficacy of new treatments for stroke in accordance to the Stroke Therapy Academic Industry Round Table criteria.

Existence of a threshold for hydroxyl radical generation independent of hypoxia in rat striatum during carbon monoxide poisoning

We examined the role of hypoxia in the carbon monoxide (CO)-induced generation of the hydroxyl radical (•OH) in the striatum, which could contribute to brain damage due to CO poisoning. Exposure of free-moving rats to 1,000 and 3,000 ppm CO or 8 and 5% O2 for 40 min caused concentration-dependent hypoxic conditions in terms of carboxyhemoglobin (COHb), deoxyhemoglobin, oxyhemoglobin, and O2 contents in arterial blood. The hypoxic conditions seemed comparable between 3,000 ppm CO and 5% O2, although alterations of pH and partial O2 pressure (PO2) were complex and concentration independent. In the striatum, CO and low O2 decreased tissue PO2 levels in a concentration-dependent and concentration-independent manner, respectively, but levels at the end of exposure were comparable among all groups. This was also the case for the increase in striatal blood flow. Although the increases in extracellular glutamate (excitatory), taurine (inhibitory), and alanine (non-neurotransmitter), in the striatum in response to CO and low O2 were complex, 3,000 ppm CO and 5% O2 had comparable effects. Thus, 3,000 ppm CO and 5% O2 seemed to induce comparable hypoxic conditions. Nevertheless, the former more strongly stimulated (•OH generation in the striatum than the latter. In addition, in contrast to low O2 which caused a concentration-dependent increase in (•OH, 1,000 ppm CO had no effect. The findings suggest that striatal •OH generation due to CO poisoning may be independent of hypoxia per se and that a threshold might exist.

Extraversion and its positive emotional core—Further evidence from neuroscience.

Converging evidence from self-report data demonstrated that extraversion and dispositional positive affect are systematically related. Several authors therefore considered positive affect as the conceptual core of extraversion. Because the ventral striatum is regarded as a core region in the physiological basis of extraversion, the present study examines the importance of this neural substrate with a special focus on positive affect. Baseline cerebral blood flow was measured in 38 participants and regressed to the extraversion and dispositional positive affect scales. Partial correlational and indirect-effects analyses indicated that striatal blood flow was no longer associated with extraversion when positive affect was statistically controlled. In contrast, when extraversion was statistically controlled, striatal blood flow was still associated with positive affect. This finding suggests that the striatal region is not a biological basis of extraversion per se. Rather, this region sustains positive affect, which in turn appears to be a core feature of extraversion.

Ventral Striatal Blood Flow is Altered by Acute Nicotine but Not Withdrawal from Nicotine

Neural mechanisms underlying the reinforcing effects of nicotine and other drugs have been widely studied and are known to involve the ventral striatum, which is part of the mesocorticolimbic dopamine system. In contrast, mechanisms of nicotine withdrawal have received less attention although subjective withdrawal likely contributes to the difficulty of quitting. The goal of this study was to determine if nicotine withdrawal was associated with alterations of cerebral blood flow (CBF) in ventral striatum. Twelve smokers, moderately dependent on nicotine, underwent MR dynamic susceptibility contrast (DSC) imaging at baseline, after overnight withdrawal from nicotine, and after nicotine replacement. DSC images were used to calculate CBF in three regions of interest: ventral striatum, thalamus, and medial frontal cortex. Subjective withdrawal symptoms were measured at each time point. In spite of significant subjective withdrawal symptoms, there was no main effect of withdrawal on CBF in the three regions. However, there was a significant correlation between the increase in withdrawal symptoms and a reduction in thalamic CBF. In contrast to withdrawal, nicotine replacement significantly increased CBF in ventral striatum. Our findings are consistent with the known role of ventral striatum in drug reward. The lack of a main effect on withdrawal, but correlation of thalamic blood flow with withdrawal symptoms suggests that more complex mechanisms mediate the subjective features of the withdrawal state.

Aggression and Quantitative MRI Measures of Caudate in Patients With Chronic Schizophrenia or Schizoaffective Disorder

Caudate dysfunction is implicated in schizophrenia. However, little is known about the relationship between aggression and caudate volumes. Forty-nine patients received magnetic resonance imaging scanning in a double-blind treatment study in which aggression was measured. Caudate volumes were computed using a semiautomated method. The authors measured aggression with the Overt Aggression Scale and the Positive and Negative Syndrome Scale. Larger caudate volumes were associated with greater levels of aggression. The relationship between aggression and caudate volumes may be related to the iatrogenic effects of long-term treatment with typical antipsychotic agents or to a direct effect of schizophrenic processes on the caudate.

Heat shock protein 72 overexpression protects against hyperthermia, circulatory shock, and cerebral ischemia during heatstroke

This study extends our earlier studies in rats by applying our heatstroke model to a new species. Additionally, transgenic mice are used to examine the role of heat shock protein (HSP) 72 in experimental heatstroke. Transgenic mice that were heterozygous for a porcine HSP70i gene ([+]HSP72), transgene-negative littermate controls ([-]HSP72), and normal Institute of Cancer Research strain mice (ICR) under pentobarbital sodium anesthesia were subjected to heat stress (40 degrees C) to induce heatstroke. In [-]HSP72 or ICR, the values for mean arterial pressure, the striatal blood flow, and the striatal PO2 after the onset of heatstroke were significantly lower than those in preheat controls. The core and brain temperatures, the extracellular concentrations of ischemic and injury markers in the striatum, and the striatal neuronal damage scores were significantly greater than those in the preheat controls. In [-]HSP72 or ICR, the body temperatures, cell ischemia content, and injury marker in the striatum were significantly higher, and the mean arterial pressure, striatal blood flow, and striatal PO2 concentration were significantly lower during heatstroke than in [+]HSP72. Accordingly, the latency and the survival times for [+]HSP72 significantly exceeded those of [-]HSP72 or ICR. These results demonstrate that the overexpression of HSP72 in multiple organs improves survival during heatstroke by reducing hyperthermia, circulatory shock, and cerebral ischemia and damage in mice.

虚血後から開始した低脳温はラット一過性前脳虚血後に生じるヒドロキシラジカルの産生を抑制する

In this study we investigated the effect of postischemic hypothermia on ROS production following transient forebrain ischemia using an in vivo microdialysis technique. Forebrain ischemia was induced by bilateral carotid artery occlusion combined with hemorrhagic hypotension for 20 minutes in male Wistar rats. The body temperature was kept at 37°C during ischemia and controlled at either 32°C or 37°C after reperfusion. The amount of hydroxyl radical produced in striatum was evaluated by measurement of 2, 3-and 2, 5-dihydroxybenzoic acid (DHBA), which is generated by salicylate hydroxylation. We also measured the extracellular concentration of xanthine and striatal blood flow by the hydrogen clearance technique. In animals whose postischemic body temperature was maintained at 37°C, the levels of 2, 3-and 2, 5-DHBA significantly increased after reperfusion. The peak levels of 2, 3-and 2, 5-DHBA were 2.9-fold 2.7-fold increase above the corresponding baseline values, respectively. Postischemic hypothermia completely inhibited the hydroxyl radical formation. Likewise, xanthine formation was also inhibited by postischemic hypothermia. In contrast, striatal cerebral blood flow was not altered by temperature modulation during reperfusion. These results suggest that inhibition of ROS production accompanied with suppression of xanthine formation is implicated in the neuroprotection of postischemic hypothermia.

Systemic sulpiride modulates striatal blood flow: relationships to spatial working memory and planning

The dopamine D2 receptor antagonist sulpiride can produce a range of cognitive deficits in normal volunteers, consistent with those seen in Parkinson's disease (PD). This, together with studies in experimental animals, implies sulpiride might be acting in the striatum. However, subtle changes in prefrontal cortex (PFC) activity are seen following l-Dopa withdrawal in PD during working memory tasks, suggesting that this may be a further site of action for dopamine D2 receptor antagonists. We have investigated the effects of sulpiride within the PFC and striatum in normal male volunteers. In two separate experiments, using identical PET regional cerebral blood flow (rCBF) methods, a combined drug and psychological challenge was performed, utilising working memory and planning tasks, and oral sulpiride 400 mg and placebo. Data were analysed using SPM99. Sulpiride increased striatal rCBF bilaterally and the working memory and planning tasks activated discrete frontoparietal networks in keeping with previous studies. However, for the working memory tasks, no changes in performance or task-induced rCBF were observed after sulpiride. For the planning task, improved performance was seen on sulpiride. Also, sulpiride attenuated striatal activity during planning (as assessed using a small volume correction, P < 0.05 corrected), and this attenuation was related to performance changes. These findings suggest that (1) sulpiride produces clear increases in striatal rCBF, (2) in contrast to previous studies no effects of sulpiride on performance of the working memory tasks or the associated neural networks were observed, and (3) sulpiride may modulate performance of more complex cognitive tasks via alterations in striatal neural activity.

Postischemic hypothermia inhibits the generation of hydroxyl radical following transient forebrain ischemia in rats.

A small reduction of body temperature during reperfusion following cerebral ischemia has been known to ameliorate neuronal injury. However, the mechanisms underlying postischemic hypothermia-induced neuroprotection are poorly understood. The burst of reactive oxygen species (ROS) formation that occurs during reperfusion has been documented to be involved in ischemic neuronal degeneration. In this study, we investigated the effect of postischemic hypothermia on ROS production following transient forebrain ischemia using an in vivo microdialysis technique. Forebrain ischemia was induced by bilateral carotid artery occlusion combined with hemorrhagic hypotension for 20 min in male Wistar rats. The body temperature was kept at 37 degrees C during ischemia and controlled at either 32 degrees C or 37 degrees C after reperfusion. The amount of hydroxyl radical produced in striatum was evaluated by measurement of 2,3- and 2,5-dihydroxybenzoic acid (DHBA), which is generated by salicylate hydroxylation. We also measured the extracellular concentration of xanthine, while determining striatal blood flow by the hydrogen clearance technique. In animals whose postischemic body temperature was maintained at 37 degrees C, the levels of 2,3- and 2,5-DHBA significantly increased after reperfusion. The peak levels of 2,3- and 2,5- DHBA were 2.9-fold and 2.7-fold increased above the corresponding baseline values, respectively. Postischemic hypothermia completely inhibited the hydroxyl radical formation. Likewise, xanthine formation was also inhibited by postischemic hypothermia. In contrast, striatal cerebral blood flow was not altered by temperature modulation during reperfusion. These results suggest that inhibition of ROS production accompanied with suppression of xanthine formation is implicated in the neuroprotection of postischemic hypothermia.

The effects of neuroleptic medications on basal ganglia blood flow in schizophreniform disorders: a comparison between the neuroleptic-naïve and medicated states

Background Previous studies indicate that basal ganglia volumes of first-episode neuroleptic-naïve patients with schizophrenia are smaller than those of normal control subjects. Subsequent exposure to neuroleptic medication appears to induce volumetric change. Possible reasons for this include differences in blood flow and metabolism between the neuroleptic-naïve and medicated states. Methods We used positron emission tomography (PET) to measure blood flow to the caudate and putamen, in a sample of 29 neuroleptic-naïve patients with schizophreniform disorders and 29 matched control subjects. We also studied a subset of the patient sample ( n = 13), comparing their “before” versus “on” medication PET scans. Results We did not find a significant difference in blood flow to the caudate and putamen between neuroleptic-naïve patients and control subjects even after controlling for whole brain blood flow; however, in the subset of 13 patients compared in the “on” versus “off” medication states, there was a statistically significant increase in blood flow to both the caudate and putamen. Conclusions Before treatment, there appears to be no difference in striatal blood flow between first-episode neuroleptic-naïve patients and healthy volunteers, but there appears to be a significant increase in blood flow to the striatum after the treatment is initiated.

Regulation of the cerebral circulation by cytochrome P450 epoxygenase activity

Cytochrome P450 epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which can dilate cerebral vessels. In glial cell cultures, glutamate stimulates the release of EETs. Thus, an astrocyte-based epoxygenase pathway could form a link in the coupling of blood flow to neuronal activity. To test this hypothesis, neuronal activation was produced by mechanical displacement of the whiskers of anesthetized rats while monitoring red cell flux by laser-Doppler flowmetry over whisker barrel sensory cortex. N-methylsulfonyl-6-(2-propargyloxyphenol) hexanamide (MS-PPOH) or miconazole, two different types of P450 epoxygenase inhibitors, were superfused over the cortical surface in different groups of rats. Both inhibitors markedly reduced the increase in cortical perfusion during whisker stimulation. To test the effect of these inhibitors on the increase in blood flow evoked by N-methyl- d-aspartate (NMDA), drugs were delivered via microdialysis probes in the striatum, while local blood flow was measured by the hydrogen clearance technique. Both MS-PPOH and miconazole blocked the increase in striatal blood flow during microdialysis perfusion of NMDA. These results support a role for P450 epoxygenase activity in the coupling of cortical blood flow to whisker stimulation and to pharmacological activation of NMDA receptors in striatum.

The effects of LY393613, nimodipine and verapamil, in focal cerebral ischaemia

This study evaluates the effects of N-{2-[bis (4-fluorophenyl)methoxy]ethyl}-1-butanamine hydrochloride (LY393613), a novel neuronal (N/P/Q-type) Ca2+ channel blocker, in ischaemia. For comparison, two commonly used L-type Ca2+ channel blockers; nimodipine and verapamil were also evaluated. Ischaemia was induced in freely moving rats by micro-injection of endothelin-1 near the middle cerebral artery. In vivo microdialysis, laser Doppler flowmetry and histology were used to monitor ischaemia. Administration of LY393613, before and after the insult, attenuated the ischaemia-induced glutamate release, but not the dopamine release. Both nimodipine and verapamil failed to affect transmitter releases significantly, when administered post-occlusion. None of the compounds tested, produced any significant change in striatal blood flow. Histology showed that ischaemic damage was significantly less in LY393613 pre-treated rats. In conclusion, LY393613, a neuronal N/P/Q-Ca2+ channel blocker, can attenuate ischaemic brain damage. The protective mechanism appears to be mainly the attenuation of the ischaemia-induced glutamate release, rather than its effect on cerebral hemodynamics.

Neurochemical changes and laser Doppler flowmetry in the endothelin-1 rat model for focal cerebral ischemia

Generalized neurotransmitter overflow into the extracellular space, after cerebral ischemia, has been suggested to contribute to subsequent neuronal death. This study aims to investigate the striatal release of the neurotransmitters dopamine (DA), glutamate (Glu) and gamma-aminobutyric acid (GABA) by means of microdialysis, in a rat model for focal transient cerebral ischemia. Ischemia was induced by the application of 120 pmol endothelin-1 (Et-1), adjacent to the middle cerebral artery (MCA) in freely moving rats. Ischemia produced a large increase in extracellular striatal DA concentrations (2400%), Glu (5500%) and GABA (800%) concentrations. Laser Doppler flowmetry in anaesthetized rats, indicated that the blood flow within the striatum decreased by 75±11%. The period of sustained drop of blood flow, was dose-dependently related to the concentration Et-1 injected. Histological analysis of brain slices, taken from anaesthetized and conscious animals, indicated a 500 pmol dose of Et-1 was required to produce a similar infarct in anaesthetized rats to a 120 pmol dose of Et-1 in freely moving rats. The immediate drop in striatal blood flow, and the prompt increase of extracellular DA, after the micro-application of Et-1, were quite striking. This suggests that the DA release, rather than the Glu overflow may be the primary event initiating the cascade of processes ultimately leading to cell death and neurological deficits.