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J H Greenberg

Publications and source records attributed to J H Greenberg.

At least 19 recordsLinked to original sources
PubMed1999

Chronic inhibition of NOS does not prevent plasticity of rat somatosensory (S1) cortex following deafferentation.

Nitric oxide (NO) has been proposed as an intercellular messenger mediating postsynaptic to presynaptic information transfer in the induction of long-term potentiation. A number of studies support the possible involvement of NO in synaptic plasticity. NO may have a role in synaptogenesis and synaptic plasticity in developing rat brain and may play a fundamental part in the process of regeneration, plasticity, and retargeting of axons following injury. We examined the possible role of NO on plasticity in the rat first somatosensory cortex with [14C]2-deoxyglucose (2-DG) autoradiography in rats treated daily with l-nitroarginine (l-NA) following neonatal unilateral vibrissae deafferentation. After 6 weeks of l-NA treatment, the local cerebral glucose utilization (LCGU) and the spatial extent of the metabolic activation following stimulation of the spared whisker was measured. NOS catalytic activity exhibited significant inhibition throughout the treatment period. Vibrissae deafferentation produced a small but not statistically significant increase of LCGU in the vibrissa activated C3 barrel, and l-NA treatment did not alter the activation of LCGU in the deafferented cortex following whisker stimulation. Additionally, l-NA treatment did not alter the area of metabolic activation on either the non-deafferented side or the deafferented side. Deafferentation produced a 298% increase in the metabolic representation of the spared C3 barrel following stimulation in the saline treated animals, a 257% increase in the chronically l-NA treated animals, and a 256% increase in the short-term treated animals, all with respect to the response in the non-deafferented cortex. Metabolic plasticity in the barrel cortex was not attenuated by l-NA treatment. These results show that nitric oxide does not play a major role on developmental cortical plasticity induced by vibrissae deafferentation in the rat.

Afferent Pathways↗
PubMed1998

Transcranial laser doppler mapping of activation flow coupling of the rat somatosensory cortex.

Signal averaged laser Doppler (LD) through a thinned skull over the rat somatosensory cortex was used to map the spatial and temporal characteristics of activation-flow coupling, the change in regional cerebral blood flow (CBF) due to neuronal activation, in response to electrical forepaw stimulation. The location of maximal changes in amplitude of the LD response was reproducibly recorded at 4-5 mm lateral to Bregma. This location is very similar but slightly posterior and lateral to results obtained from electrophysiological, magnetic resonance imaging (MRI), and optical imaging studies. The latency of the activation-flow coupling (AFC) response was inversely correlated to response amplitude, with shorter latencies at positions of maximal amplitude.

Animals↗
PubMed1998

Signal averaged laser Doppler measurements of activation-flow coupling in the rat forepaw somatosensory cortex.

Regional alterations in cerebral blood flow (CBF) are widely used as a surrogate for neuronal function based on an intact coupling between changes in regional CBF and metabolism, activation-flow coupling (AFC). To further investigate parameters affecting AFC, we have implemented a rat model with electrical forepaw stimulation under alpha-chloralose anesthesia using laser Doppler (LD) measurements of flow parameters through thinned skull over contralateral somatosensory cortex. Signal averaging of the LD response was used to improve reproducibility. A characteristic flow response to electrical forepaw stimulation was reliably recorded from the somatosensory cortex using signal averaging. Stimulation at 5 Hz maximized the LD response, and constant current stimulation up to 1 mA did not induce changes in systemic blood pressure. The shape of the flow response consisted of an initial peak followed by a steady state plateau phase which was observed for stimulation durations longer than 4 s. When individual LD parameters of velocity, red blood cell concentration (CRBC), and cerebral blood flow (CBF) were compared, changes in LDCBF were primarily attributable to changes in LDvelocity rather than LDCRBC. This finding was also observed during hypercapnia. Characterization of AFC in the model provides a background for future studies of the effects of pharmacological manipulation or pathophysiological states.

Animals↗
PubMed1997

Distribution of N(omega)-nitro-L-arginine following topical and intracerebroventricular administration in the rat.

The distribution of the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine (L-NA), in the rat brain following either topical or intracerebroventricular application was examined using 14C-labeled L-NA. Two hours after topical application, the concentration of L-NA 1 mm below the surface was approximately 20% of the concentration at the surface, and less than 3% at 2 mm below the cortical surface. L-NA infused into the lateral cerebral ventricle distributes only in regions in close proximity to the ventricle even 8 h after administration. Consequently, intracerebroventricular administration of nitric oxide synthase inhibitors may not be useful if global inhibition of nitric oxide synthase is desired.

Administration, Topical↗
PubMed1997

N-(N-benzylpiperidin-4-yl)-2-[18F]fluorobenzamide: a potential ligand for PET imaging of sigma receptors.

Four nitro- and fluorobenzamides (1-4) have been synthesized in good yields from nitro- and fluoro-substituted benzoyl chloride with 4-amino-1-benzylpiperidine. In vitro studies showed that these compounds have high affinities to sigma receptors. N-(N-Benzylpiperidin-4-yl)-2-fluorobenzamide (3), in particular, bound to sigma receptors with high affinity (Ki = 3.4 nM, guinea pig brain membranes) and high selectivity (sigma-2/sigma-1 = 120). It was, therefore, labeled with 18F and evaluated as a sigma receptor radioligand. N-(N-Benzylpiperidin-4-yl)-2-[18F]fluorobenzamide (3a) was synthesized in one step by nucleophile substitution of the 2-nitro precursor (1) with [18F]fluoride in DMSO at 140 degrees C for 20 min followed by purification with HPLC in 4-10% yield (decay corrected). The synthesis time was 90 min and the specific activity was 0.4-1.0 Ci/mumol. Tissue distribution in mice revealed that the uptakes of 3a in the brain, heart, liver, lungs, spleen, kidneys and small intestine were high, and the radioactivity in these organs remained constant from 60 to 120 min post-injection. The radioactivity in the bone did not significantly increase, suggesting in vivo defluorination may not be the major route of metabolism of 3a in mice. Blocking studies with haloperidol in rats indicated that the uptake of compound 3a in the rat brain was selective to haloperidol-sensitive sigma sites. These results suggest that compound 3a is a potent sigma receptor radioligand and may be a potential ligand for PET imaging of sigma receptors in humans.

Animals↗
PubMed1997

Neuroprotective effects of inhibiting poly(ADP-ribose) synthetase on focal cerebral ischemia in rats.

Poly(adenosine 5'-diphosphoribose) synthetase (PARS) has been described as an important candidate for mediation of neurotoxicity by nitric oxide. In the current study, we demonstrate for the first time that in vivo administration of a potent PARS inhibitor, 3,4-dihydro 5-[4-1(1-piperidinyl) butoxy]-1(2H)-isoquinolinone, leads to a significant reduction of infarct volume in a focal cerebral ischemia model in the rat. Focal cerebral ischemia was produced by cauterization of the right distal middle cerebral artery (MCA) with bilateral temporary common carotid artery occlusion for 90 minutes. 3,4-Dihydro 5[4-(1-piperidinyl) butoxy]-1(2H)-isoquinolinone was dissolved in dimethyl sulfoxide and injected intraperitoneally. Animals were treated 2 hours before MCA occlusion (control, n = 14; 5 mg/kg, n = 7; 10 mg/kg, n = 7; 20 mg/kg, n = 7; 40 mg/kg, n = 7), and 2 hours after MCA occlusion (same doses as before treatment). Twenty-four hours after MCA occlusion, the total infarct volume was measured using 2,3,5-triphenyltetrazolium chloride. Inhibition of PARS leads to a significant decrease in the damaged volume in the 5 mg/kg-treated group (106.7 +/- 23.2 mm3; mean +/- SD, P < 0.002), the 10 mg/kg-treated group (76.4 +/- 16.8 mm3, P < 0.001), and the 20 mg/kg-treated group (110.2 +/- 42.0 mm3, P < 0.02) compared with the control group (165.2 +/- 34.0 mm3). The substantial reduction in infarct volume indicates that the activation of PARS may play an important role in the pathogenesis of brain damage in cerebral ischemia through intracellular energy depletion.

Animals↗
PubMed1996

Radiosynthesis and biodistribution of the S-[18F]fluoroethyl analog of McN5652.

[11C]McN5652 has been reported to exhibit favorable properties as a PET radiotracer for studying serotonin uptake sites. However, the use of this radiotracer may be limited by the short half-life of11C. To obtain a tracer with longer physical half-life, we have synthesized the S-[18F]fluoroethyl analog of McN5652 (trans-1,2,3,5,6,10b-hexahydro-6-[4-([18F]fluoroethylthio)-phenyl] pyrrolo-[2,1-a]-isoquinoline) ([18F]FEMcN) and evaluated as a PET radiotracer for imaging serotonin uptake sites. The radiosynthesis was performed via a one-pot, two-step procedure. In the first step, 1-bromo-2-[18F]fluoroethane was prepared from 2-bromoethyl triflate and K18F/Kryptofix 2.2.2. in THF at room temperature. The second step, the S-fluoroalkylation of the normethyl McN5652, a thiol, was carried out, without isolating the 1-bromo-2-[18F]fluoroethane, by adding the normethyl McN5652 to the reaction vial, which was warmed at 45 degrees C for 1 min. The fluoroalkylation reaction proceeded quickly, giving [18F]FEMcN in an average overall radio-chemical yield of 13 +/- 7%. The specific activity was 1593 +/- 625 mCi/mumol. Ex vivo autoradiographic studies revealed that [18F]FEMcN accumulated into regions with high densities of 5-HT uptake sites such as hypothalamus, substantia nigra, and raphe nuclei. With blockade by nitroquipazine, a selective and highly potent 5-HT uptake blocker, the activity level in these regions was close to that in regions low in 5-HT uptake sites such as cerebellum, suggesting that this radiotracer binds specifically to 5-HT uptake sites. The regional distribution of [18F]FEMcN at 60 min postinjection correlated with the distribution of [11C]McN5652 reported in the literature. The specific binding of this radiotracer determined as the difference in radioactivity accumulation with and without blocking by the 5-HT uptake blocker agreed with the distribution of the number of 5-HT uptake sites measured in vitro. Thus, 5-HT uptake sites were visualized in vivo with [18F]FEMcN. However, comparison with the in vivo behavior of [11C]McN5652 indicated less favorable properties of [18F]FEMcN as a PET radiotracer for imaging 5-HT uptake sites, including lower blood-brain barrier penetration and lower target-to-nontarget ratios.

Animals↗
PubMed1996

Regional heterogeneity and differential vulnerability of cerebral and spinal vascular CO2-responsiveness during graded haemorrhagic hypotension.

Regional inhomogeneity of cerebrovascular CO2-sensitivity as well as its changes at three different levels of standardized haemorrhagic hypotension were studied in ten distinct brain and spinal cord regions of anesthetized, ventilated cats. Regional cerebral blood flow was measured with radiolabelled microspheres in hypocapnic, normocapnic, and hypercapnic conditions, and CO2-responsiveness was determined from the equation of the slopes of the best fit regression lines to the obtained flow values. It was concluded that in normotensive, normoxic cats response of the cerebral and spinal vessels to PaCO2 alterations can be assigned to four major categories. The CO2-responsiveness of a brain region is not solely determined by the rate of its basal steady state blood flow: CO2-reactivity of the hypothalamus was significantly different from that of any other investigated regions with almost identical steady state flow values. Vulnerability of the cerebrovascular CO2-sensitivity during hypotension was different from region to region, with the vessels of the pons-medulla oblongata region being the most sensitive to haemorrhage. Reduced regional cerebral and spinal CO2-responsiveness during haemorrhage is not a consequence of a reduced L-arginine supply for nitric oxide generation since administration of an excess amount of the precursor L-arginine failed to restore the haemorrhage-induced reduction of regional CO2-sensitivity at the 60 mm Hg mean arterial pressure level.

Animals↗
PubMed1995

PET imaging studies of dopamine D2 receptors: comparison of [18F]N-methylspiperone and the benzamide analogues [18F]MABN and [18F]MBP in baboon brain.

A series of positron emission tomography (PET) imaging studies was conducted in a baboon with the benzamide derivatives [18F]2,3-dimethoxy-N-[9-(4-fluorobenzyl)-9-azabicyclo[3.3.1]non an-3 beta-yl]benzamide ([18F]MABN) and [18F]2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4-yl]be nza mide ([18F]MBP). Studies were also conducted with the butyrophenone [18F]N-methylspiperone (NMSP) for comparison. Tissue-time activity curves of [18F]MABN are similar to those of [18F]NMSP since both compounds displayed approximately the same uptake in the basal ganglia and displayed irreversible binding kinetics in vivo. However, the rapid rate of clearance from the cerebellum and high basal ganglia:cerebellum ratio of [18F]MABN indicate that this compound has a much lower amount of nonspecific binding than [18F]NMSP. [18F]MBP displayed a higher uptake in the basal ganglia relative to [18F]NMSP and [18F]MABN and exhibited reversible binding kinetics in vivo. This property of [18F]MBP is desirable since the uptake of radioactivity in D2-rich ligands is less likely to be influenced by changes in cerebral blood flow. The current data suggest that both [18F]MABN and [18F]MBP are promising ligands for studying dopamine D2 receptors with PET.

Animals↗
PubMed1995

Failure of levemopamil to improve histological outcome following temporary occlusion of the middle cerebral artery in cats.

Levemopamil, a novel calcium channel blocker with antagonistic action on serotonin S2-receptors has been reported to be a promising compound for therapy in cerebral ischemia. This data has been obtained in the rat only, and it is of interest to determine if these beneficial effects are present in other models of ischemia in other species. The present study was therefore designed to examine its effect on histological outcome and changes in EEG after focal cerebral ischemia and reperfusion in the cat. Focal cerebral ischemia was induced by a reversible 1 hour occlusion of the middle cerebral artery followed by reperfusion of the brain. Six hours after the induction of the insult, the brain was perfusion-fixed and evaluated for histological damage by light microscopy. In 8 animals an intravenous infusion of levemopamil was initiated 5 minutes after middle cerebral artery occlusion at a rate of 4 mg/kg/h for 15 min and then at 0.6 mg/kg/h until the end of the study. A control group (n = 7) received a similar infusion of saline. The EEG amplitude did not differ between the two groups at any point of the study. The area of ischemic damage in the sections obtained for histological examination at 1-mm intervals, as well as the total volume of ischemic damage for both groups (treated: 1.33 cm3; untreated: 0.97 cm3) also did not show any significant differences. These results indicate that postischemic treatment with levemopamil at this dose, and in this model of focal cerebral ischemia and reperfusion, does not attenuate the ischemic damage.

Animals↗
PubMed1995

Effects of central inhibition of nitric oxide synthase on focal cerebral ischemia in rats.

We have investigated whether central inhibition of nitric oxide synthase (NOS) could modify the tissue damage of focal cerebral ischemia produced by occlusion of the middle cerebral artery (MCA) in rats. NG-Nitro-L-arginine methyl ester (L-NAME) was administered intracerebroventricularly at two doses 15 min prior to occlusion of the MCA, as well as 4 and 24 h following occlusion. After the injection of L-NAME, the catalytic activity of the constitutive NOS, considered to be mainly neuronal, was effectively suppressed in the subcortical gray matter bilaterally, but not in the ischemic territory. Seven days after the MCA occlusion, the brains were evaluated for histopathologic damage. High-dose administration of L-NAME (120 micrograms/kg 15 min prior to MCA occlusion, followed by 150 micrograms/kg 4 and 24 h after occlusion) produced an enlargement of the infarct area and increased the volume of ischemic damage. These results indicate that extensive inhibition of NOS by a central route can increase the cerebral infarct size in focal ischemia even if NOS is not inhibited in the ischemic tissue and suggest that NO may also play a potentially beneficial role as well as a neurodestructive role in the pathophysiological mechanisms of focal cerebral ischemia.

Amino Acid Oxidoreductases↗
PubMed1995

Clinicopathological observations in middle cerebral artery occlusion in the cat.

This study was designed to investigate the relationships among neurological deficits, changes in the electroencephalogram (EEG) and morphological damage over a one week period following temporary occlusion (2 h) of the middle cerebral artery (MCA) in the cat. The animals were grouped into mild, moderate, and severe stroke based on the EEG alterations produced 30 min after the MCA occlusion. All three grades of stroke showed a precipitous fall in mean EEG amplitude followed by a recovery during a 4 h recirculation period. Over the subsequent 7 days there was a gradual secondary depression in the EEG amplitude. Post-operatively, a secondary fall in EEG amplitude in the contralateral hemisphere was also noted in all stroke groups corresponding to the clinical phenomenon of 'diaschisis'. The overall neurological score differed significantly among the severe, moderate, and mild stroke groups. The neurological deficits on the 7th day were highly correlated with the degree of morphological damage. Additionally, the reduction of EEG was also well correlated with the pathological data. This stroke model in the cat has provided important data concerning the restitution of brain function following chronic focal ischaemia.

Animals↗
PubMed1994

Prolonged effects of MK-801 in the cat during focal cerebral ischemia and recovery: survival, EEG activity and histopathology.

Previously we reported an improvement in histological outcome in cats treated with MK-801 shortly after the induction of temporary middle cerebral artery occlusion, and examined after 2 h of ischemia followed by 4 h of reperfusion. This study investigates the prolonged effects of the same drug treatment. Focal cerebral ischemia was produced in 34 cats by temporary occlusion of the left middle cerebral artery for 2 h. Stroke severity was determined using the ratio of the EEG amplitude from the ipsilateral to that of the contralateral hemisphere. Thirty minutes after the onset of ischemia, cats were treated i.v. with either 1 mg/kg MK-801 or saline. Electrocortical activity of the animals who survived were followed for 6 days postocclusion at which point they were sacrificed for histopathological analysis. Twelve of the animals died during recovery, of which 4 were MK-801 treated, and 8 were saline controls. The EEG ratios in the non-surviving animals were more depressed than in the animals that survived, whereas the depression in the EEG amplitude in both the treated and the control surviving animals was equal. Among the survivors no reduction in infarct size with MK-801 treatment was observed. Thus treatment with MK-801 in the middle cerebral artery occlusion model in the cat leads to a significant increase in the rate of survival (P < 0.05), but no prolonged improvement in late histopathology, in contrast with acute histological findings using this model. MK-801 treatment may be shifting the stroke model towards the survival of animals with larger infarcts. Histological recovery during prolonged reperfusion may eliminate the early neuroprotective effects seen with MK-801 treatment.

Analysis of Variance↗
PubMed1994

Correlation between 99mTc-bicisate and regional CBF measured with iodo-[14C]antipyrine in a primate focal ischemia model.

The need for an agent to quantitatively measure regional cerebral blood flow in humans using single photon emission computed tomography has led to the development of a new 99mTc-labeled agent: bicisate (ethyl cysteinate dimer). We have utilized an acute stroke model in the baboon to examine the ability of this agent to quantitatively measure regional cerebral blood flow in ischemic tissue. One hour after occlusion of either the left anterior cerebral or the middle cerebral artery, 99mTc-bicisate was administered intravenously, followed 20 min later by the measurement of local cerebral blood flow using iodo-[14C]antipyrine. With use of double-label autoradiography, the distribution of 99mTc-bicisate was correlated with the local cerebral blood flow images. A cerebral blood flow parameter was calculated from the 99mTc-bicisate tissue distribution and the arterial blood tracer concentration using an indicator fractionation model. For cerebral blood flows above approximately 40-50 ml 100 g-1 min-1, 99mTc-bicisate underestimates cerebral blood flow by as much as 20%, while for blood flows below approximately 15 ml 100 g-1 min-1, blood flow is overestimated by the 99mTc-bicisate distribution by an average of 3-4 ml 100 g-1 min-1. This apparent hyperfixation at very low blood flows may be related to a higher extraction of this tracer by ischemic tissue.

Animals↗