Central Serotonin Depletion. Effect on Blood Pressure during Anesthesia. John S. Althaus, MS,; Ju... more Central Serotonin Depletion. Effect on Blood Pressure during Anesthesia. John S. Althaus, MS,; Judy J. Beckman, BS and; Edward D. Miller jr, MD. Department of Anesthesiology, University of Virginia, Charlottesville, Virginia. Abstract. ...
A novel group of antioxidant compounds, the pyrrolopyrimidines, has been discovered recently. Man... more A novel group of antioxidant compounds, the pyrrolopyrimidines, has been discovered recently. Many of these possess significantly improved oral bioavailability (56-70% in rats), increased efficacy and potency in protecting cultured neurons against iron-induced lipid peroxidative injury and as much as a 5-fold increase in brain uptake compared with the 21-aminosteroid antioxidant compound, tirilazad mesylate (U-74006F), described earlier. They appear to quench lipid peroxidation reactions by electron-donating and/or radical-trapping mechanisms. Several compounds in the series, such as U-101033E and U-104067F, demonstrate greater ability than tirilazad to protect the hippocampal CA1 region in the gerbil transient (5-min) forebrain ischemia model. Delaying treatment until 4 hr after the ischemic insult still results in significant CA1 neuronal protection. U-101033E is still effective in salvaging a portion of the CA1 neuronal population when the ischemic duration is extended to 10 min. In addition, U-101033E has been found to be protective in the context of focal cerebral ischemia, reducing infarct size in the mouse permanent middle cerebral artery occlusion model, in contrast to tirilazad which is minimally effective. These results suggest that antioxidant compounds with improved brain parenchymal penetration are better able to limit certain types of ischemic brain damage than those which are localized in the cerebral microvasculature. However, the activity of U-101033E in improving early post-traumatic recovery in mice subjected to severe concussive head injury is similar to that of tirilazad. Last, the oral bioavailability of many pyrrolopyrimidines suggests that they may be useful for certain chronic neurodegenerative disorders in which lipid peroxidation plays a role.
Our studies examined the role of dopamine D4 receptors in the induction of behavioral sensitizati... more Our studies examined the role of dopamine D4 receptors in the induction of behavioral sensitization to amphetamine (Amp) and accompanying neurochemical and molecular adaptive responses using a highly selective D4 antagonist, PNU-101387G. Behavioral sensitization to an acute challenge of Amp (2 mg/kg, s.c.) was observed in rats pretreated with five daily doses of Amp (2 mg/kg/d, s.c.) followed by 7-day withdrawal. Interestingly, coadministration of PNU-101387G with Amp during pretreatment completely blocked the sensitized response to an acute Amp challenge. The behavioral sensitization and its blockade by the D4 antagonist were observed in the absence of significant differences in cerebellar Amp levels among the various pretreatment groups. Accompanying behavioral sensitization were two postsynaptic neuroadaptive responses: reduction in the ability of Amp to induce c-fos gene expression in the infralimbic/ventral prelimbic cortex and NT/N mRNA in the accumbal shell. However, concurrent blockade of D4 receptors during Amp pretreatment prevented the refractoriness in c-fos and NT/N responsiveness to acute Amp. We observed also a presynaptic neuroplastic response associated with the behavioral sensitization: a significant augmentation in the ability of Amp to increase extracellular dopamine concentrations in the nucleus accumbens shell. As with the behavioral sensitization and associated postsynaptic adaptive responses, concurrent administration of PNU-101387G with Amp during pretreatment blocked the augmentation in Amp-induced dopamine release. Taken together, these data demonstrate that dopamine D4 receptors play an important role in the induction of behavioral sensitization to Amp and accompanying adaptations in pre- and postsynaptic neural systems associated with the mesolimbocortical dopamine projections.
Aminophylline reduces hypoxic ventilatory depression in newborn piglets and can enhance the relea... more Aminophylline reduces hypoxic ventilatory depression in newborn piglets and can enhance the release of catecholamines (CATs), which in turn may stimulate ventilation. To determine if the effect of aminophylline on ventilation was due to the release of CATs, we measured plasma CATs and ventilation in two groups of spontaneously breathing newborn piglets less than 4 days old, treated with either aminophylline (n = 7) or normal saline solution (n = 6) during both normoxia and hypoxia. The piglets were anesthetized with ketamine and xylazine and intubated, and the femoral artery was catheterized. Epinephrine and norepinephrine were measured before and 30 minutes after treatment with aminophylline (15 mg/kg) or normal saline. The animals were exposed to 10% oxygen and the CATs again measured after 5 minutes of hypoxia. Respiratory rate, expiratory flow integrated to minute ventilation (VE), heart rate, and blood pressure were continuously recorded. CATs were assayed by high‐pressure liquid chromatography with electrochemical detection. Treatment with aminophylline during normoxia was associated with an increase in tidal volume. During hypoxia, treatment with aminophylline prevented a fall in VF and respiratory rate seen in the normal saline group. Epinephrine and norepinephrine increased during hypoxia, but there was no difference between the groups at 5 minutes. In our model the increase in CATs observed during hypoxia was not enhanced by aminophylline. This is consistent with the hypothesis that some mechanism other than catecholamine release is responsible for the effect of aminophylline in reducing neonatal hypoxic respiratory depression.
We have examined the neuroprotective efficacy of the selective dopamine (DA) D2/D3 receptor agoni... more We have examined the neuroprotective efficacy of the selective dopamine (DA) D2/D3 receptor agonist pramipexole in two models of nigrostriatal (NS) degeneration. The first involves the delayed (28-day) postischemic retrograde NS degeneration that takes place in gerbils following a 10-min episode of bilateral carotid arterial occlusion-induced forebrain ischemia. In vehicle (40% hydroxypropyl cyclodextrin)-treated male gerbils, there was a 40-45% loss of NS cell bodies in the pars compacta and pars reticulata (TH immunohistochemistry and Cresyl violet histochemistry) by 28 days after ischemia/reperfusion. Daily postischemic oral dosing (1 mg/kg p.o., b.i.d., beginning at 1 h after insult) decreased the 28-day postischemic loss of NS DA neurons by 36% (P < 0.01 vs. vehicle-treated). The effect was specific for dopamine neurons since no significant salvage of hippocampal CA1 neurons was observed. In a second model, pramipexole's effects were examined on methamphetamine-induced (10 mg/kg, i.p. X 4, each 2 h apart) NS degeneration in male Swiss-Webster mice. In vehicle-treated mice, there was a 40% loss of NS neurons by day 5. In contrast, pramipexole dosing (1 mg/kg, p.o., 1 h after the last methamphetamine dose, plus daily) attenuated the NS degeneration from 40% to only 8% (P < 0.00001 vs. vehicle). We postulated that pramipexole acts in both of these models to reduce the elevated DA turnover and the associated elevation in hydroxyl radical production secondary to increased MAO activity that could be responsible for oxidative damage to the NS neurons. Indeed, in the gerbil ischemia model, we documented by HPLC-ECD a 135% postreperfusion increase in DA turnover (DOPAC + HVA/DA) at 5 min after reperfusion. Pramipexole at the 1 mg/kg, p.o., dose level was able to significantly reduce the increased DA turnover, but by only 16%. Thus, it is conceivable that other mechanisms may also contribute to pramipexole's dopaminergic neuroprotection. Based on a preliminary examination of pramipexole's oxidation potential, it appears that the compound may possess significant intrinsic antioxidant properties that might contribute to its neuroprotective effects.
Central Serotonin Depletion. Effect on Blood Pressure during Anesthesia. John S. Althaus, MS,; Ju... more Central Serotonin Depletion. Effect on Blood Pressure during Anesthesia. John S. Althaus, MS,; Judy J. Beckman, BS and; Edward D. Miller jr, MD. Department of Anesthesiology, University of Virginia, Charlottesville, Virginia. Abstract. ...
A novel group of antioxidant compounds, the pyrrolopyrimidines, has been discovered recently. Man... more A novel group of antioxidant compounds, the pyrrolopyrimidines, has been discovered recently. Many of these possess significantly improved oral bioavailability (56-70% in rats), increased efficacy and potency in protecting cultured neurons against iron-induced lipid peroxidative injury and as much as a 5-fold increase in brain uptake compared with the 21-aminosteroid antioxidant compound, tirilazad mesylate (U-74006F), described earlier. They appear to quench lipid peroxidation reactions by electron-donating and/or radical-trapping mechanisms. Several compounds in the series, such as U-101033E and U-104067F, demonstrate greater ability than tirilazad to protect the hippocampal CA1 region in the gerbil transient (5-min) forebrain ischemia model. Delaying treatment until 4 hr after the ischemic insult still results in significant CA1 neuronal protection. U-101033E is still effective in salvaging a portion of the CA1 neuronal population when the ischemic duration is extended to 10 min. In addition, U-101033E has been found to be protective in the context of focal cerebral ischemia, reducing infarct size in the mouse permanent middle cerebral artery occlusion model, in contrast to tirilazad which is minimally effective. These results suggest that antioxidant compounds with improved brain parenchymal penetration are better able to limit certain types of ischemic brain damage than those which are localized in the cerebral microvasculature. However, the activity of U-101033E in improving early post-traumatic recovery in mice subjected to severe concussive head injury is similar to that of tirilazad. Last, the oral bioavailability of many pyrrolopyrimidines suggests that they may be useful for certain chronic neurodegenerative disorders in which lipid peroxidation plays a role.
Our studies examined the role of dopamine D4 receptors in the induction of behavioral sensitizati... more Our studies examined the role of dopamine D4 receptors in the induction of behavioral sensitization to amphetamine (Amp) and accompanying neurochemical and molecular adaptive responses using a highly selective D4 antagonist, PNU-101387G. Behavioral sensitization to an acute challenge of Amp (2 mg/kg, s.c.) was observed in rats pretreated with five daily doses of Amp (2 mg/kg/d, s.c.) followed by 7-day withdrawal. Interestingly, coadministration of PNU-101387G with Amp during pretreatment completely blocked the sensitized response to an acute Amp challenge. The behavioral sensitization and its blockade by the D4 antagonist were observed in the absence of significant differences in cerebellar Amp levels among the various pretreatment groups. Accompanying behavioral sensitization were two postsynaptic neuroadaptive responses: reduction in the ability of Amp to induce c-fos gene expression in the infralimbic/ventral prelimbic cortex and NT/N mRNA in the accumbal shell. However, concurrent blockade of D4 receptors during Amp pretreatment prevented the refractoriness in c-fos and NT/N responsiveness to acute Amp. We observed also a presynaptic neuroplastic response associated with the behavioral sensitization: a significant augmentation in the ability of Amp to increase extracellular dopamine concentrations in the nucleus accumbens shell. As with the behavioral sensitization and associated postsynaptic adaptive responses, concurrent administration of PNU-101387G with Amp during pretreatment blocked the augmentation in Amp-induced dopamine release. Taken together, these data demonstrate that dopamine D4 receptors play an important role in the induction of behavioral sensitization to Amp and accompanying adaptations in pre- and postsynaptic neural systems associated with the mesolimbocortical dopamine projections.
Aminophylline reduces hypoxic ventilatory depression in newborn piglets and can enhance the relea... more Aminophylline reduces hypoxic ventilatory depression in newborn piglets and can enhance the release of catecholamines (CATs), which in turn may stimulate ventilation. To determine if the effect of aminophylline on ventilation was due to the release of CATs, we measured plasma CATs and ventilation in two groups of spontaneously breathing newborn piglets less than 4 days old, treated with either aminophylline (n = 7) or normal saline solution (n = 6) during both normoxia and hypoxia. The piglets were anesthetized with ketamine and xylazine and intubated, and the femoral artery was catheterized. Epinephrine and norepinephrine were measured before and 30 minutes after treatment with aminophylline (15 mg/kg) or normal saline. The animals were exposed to 10% oxygen and the CATs again measured after 5 minutes of hypoxia. Respiratory rate, expiratory flow integrated to minute ventilation (VE), heart rate, and blood pressure were continuously recorded. CATs were assayed by high‐pressure liquid chromatography with electrochemical detection. Treatment with aminophylline during normoxia was associated with an increase in tidal volume. During hypoxia, treatment with aminophylline prevented a fall in VF and respiratory rate seen in the normal saline group. Epinephrine and norepinephrine increased during hypoxia, but there was no difference between the groups at 5 minutes. In our model the increase in CATs observed during hypoxia was not enhanced by aminophylline. This is consistent with the hypothesis that some mechanism other than catecholamine release is responsible for the effect of aminophylline in reducing neonatal hypoxic respiratory depression.
We have examined the neuroprotective efficacy of the selective dopamine (DA) D2/D3 receptor agoni... more We have examined the neuroprotective efficacy of the selective dopamine (DA) D2/D3 receptor agonist pramipexole in two models of nigrostriatal (NS) degeneration. The first involves the delayed (28-day) postischemic retrograde NS degeneration that takes place in gerbils following a 10-min episode of bilateral carotid arterial occlusion-induced forebrain ischemia. In vehicle (40% hydroxypropyl cyclodextrin)-treated male gerbils, there was a 40-45% loss of NS cell bodies in the pars compacta and pars reticulata (TH immunohistochemistry and Cresyl violet histochemistry) by 28 days after ischemia/reperfusion. Daily postischemic oral dosing (1 mg/kg p.o., b.i.d., beginning at 1 h after insult) decreased the 28-day postischemic loss of NS DA neurons by 36% (P < 0.01 vs. vehicle-treated). The effect was specific for dopamine neurons since no significant salvage of hippocampal CA1 neurons was observed. In a second model, pramipexole's effects were examined on methamphetamine-induced (10 mg/kg, i.p. X 4, each 2 h apart) NS degeneration in male Swiss-Webster mice. In vehicle-treated mice, there was a 40% loss of NS neurons by day 5. In contrast, pramipexole dosing (1 mg/kg, p.o., 1 h after the last methamphetamine dose, plus daily) attenuated the NS degeneration from 40% to only 8% (P < 0.00001 vs. vehicle). We postulated that pramipexole acts in both of these models to reduce the elevated DA turnover and the associated elevation in hydroxyl radical production secondary to increased MAO activity that could be responsible for oxidative damage to the NS neurons. Indeed, in the gerbil ischemia model, we documented by HPLC-ECD a 135% postreperfusion increase in DA turnover (DOPAC + HVA/DA) at 5 min after reperfusion. Pramipexole at the 1 mg/kg, p.o., dose level was able to significantly reduce the increased DA turnover, but by only 16%. Thus, it is conceivable that other mechanisms may also contribute to pramipexole's dopaminergic neuroprotection. Based on a preliminary examination of pramipexole's oxidation potential, it appears that the compound may possess significant intrinsic antioxidant properties that might contribute to its neuroprotective effects.
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