Biomedical subjects

E D Hall

Publications and source records attributed to E D Hall.

At least 37 records · Page 2Linked to original sources

PubMed1998

Infant rat model of the shaken baby syndrome: preliminary characterization and evidence for the role of free radicals in cortical hemorrhaging and progressive neuronal degeneration.

Infants subjected to repeated episodes of violent shaking develop brain damage characterized by intracranial hemorrhage and progressive cortical atrophy. We have developed an animal model that mimics this pathological state and investigated its etiology and treatment. Anesthetized male rats, 6 days of age, were subjected to one episode of shaking per day for 3 consecutive days. Separate groups of rats were sacrificed 1 h postinjury on the third day of shaking for HPLC quantification of cortical .OH and vitamin E levels, and histological assessment of cortical hemorrhaging. Additional groups were sacrificed 7 or 14 days postinjury to demonstrate progressive neuronal degeneration via cortical wet weight comparisons. In comparison to noninjured shams, the results indicated that cortical vitamin E and .OH levels rose 53.7% (p < 0.005) and 457.1% (p < 0.001), respectively, in shaken infant rats. Brain histologies revealed a moderate-to-severe degree of cortical hemorrhaging in these animals 1 h postinjury. By 7 and 14 days postinjury, there was a 13.3% and 28.7% (p < 0.0001 vs. sham) loss of cortical tissue in shaken infants, respectively, indicating progressive neuronal degeneration. Treatment with 10 mg/kg (ip) of the 21-aminosteroid antioxidant, tirilazad mesylate, 10 min before and 2 h after each episode of shaking, resulted in a 53.1% attenuation of cortical .OH levels and a 34.9% decrease in brain hemorrhaging (p < 0.05 vs. vehicle). Tirilazad treatment did not, however, significantly effect cortical vitamin E concentrations at 1 h postinjury or the extent of progressive neuronal degeneration at either 7 or 14 days postinjury. The present animal model mimics the brain pathology seen in abused children. Our observation that tirilazad mesylate, an antioxidant-lipid peroxidation inhibitor, significantly reduces cortical .OH levels and brain hemorrhaging in shaken infant rats supports a role for oxygen radicals in the pathophysiology of this type of CNS injury. The failure of tirilazad to block progressive cortical degeneration suggests that mechanisms other than free radicals may be of prime importance in the mediation of this aspect of the pathology.

Age Factors↗

PubMed1998

Tirilazad widens the therapeutic window for riluzole-induced attenuation of progressive cortical degeneration in an infant rat model of the shaken baby syndrome.

Our infant rat model of traumatic subarchnoid hemorrhage combines violent shaking and hypoxia to produce subdural hemorrhaging and progressive cortical degeneration similar to that seen in victims of the shaken baby syndrome. Anesthetized, 6-day-old male rats were subjected to one episode of shaking under hypoxic conditions. Brain histologies revealed moderate-to-severe cortical hemorrhaging at 48 h postinjury and progressive cortical degeneration, as indicated by a 15.3% and 20.2% reduction in cortical wet weight, at 7 and 14 days postinjury, respectively. The purpose of the present study was to assess the effects of two antioxidant lipid peroxidation inhibitors (tirilazad mesylate and PNU-101033E), and the glutamate release inhibitor (riluzole), upon the brain pathology seen in this model. A significant, 54.3-75.3%, reduction in cortical hemorrhaging was observed in rats that were treated with a total of three doses of tirilazad (10 mg/kg, i.p.): 10 min before or 5-30 min after injury, and again at 2 and 24 h postinjury (p < 0.01 vs. vehicle). However, treatment with tirilazad or the more potent, brain-penetrating pyrrolopyrimidine, PNU-101033E (10 min before plus 2, 24, 48, and 72 h after), did not attenuate the progressive cortical degeneration typically seen at 14 days postinjury. These results suggest that free radicals play an important role in the pathophysiology of secondary brain hemorrhaging due to shaking + hypoxia, but may not be critical in the mediation of the subsequent neurodegeneration. Rather, glutamate neurotoxicity may be a key factor here. This is suggested by our observation that the glutamate release inhibitor, riluzole, significantly reduced cortical degeneration when it was administered up to 1 h postinjury in the present model. Specifically, the cortical wet weights of rats treated with 8 mg/kg riluzole (i.p.) 10 min before or 1 h after shaking + hypoxia (and again at 24 h postinjury) were 95.3% and 97.4% of noninjured controls, respectively, at 14 days postinjury (p < 0.02 vs. vehicle). Riluzole treatment beyond 1 h (e.g., 2 or 4 h postinjury) did not reduce the neurodegeneration. Lastly, we attempted to demonstrate that the therapeutic window for riluzole-induced attenuation of cortical degeneration could be extended beyond 1 h through the use of combination therapy. In this experiment, rat pups were treated with 10 mg/kg tirilazad (i.p.) at 30 min postinjury followed by 8 mg/kg riluzole (i.p.) at 4 and 24 h postinjury. At 14 days postinjury, the cortical wet weights of these rats were 94.5% of noninjured controls, thus demonstrating significant neuroprotection (p < 0.05 vs. vehicle) and a widening of the therapeutic window from 1 to 4 h in length. These results suggest that early attenuation of free radical-induced lipid peroxidation may slow down the biochemical cascade of events related to glutamate-induced excitotoxicity and, in doing so, prolong the time during which a glutamate release inhibitor, such as riluzole, is effective.

Age Factors↗

PubMed1998

Neuroprotective efficacy and mechanisms of novel pyrrolopyrimidine lipid peroxidation inhibitors in the gerbil forebrain ischemia model.

A brief period of bilateral carotid occlusion (BCO)-induced forebrain ischemia in gerbils triggers neuronal degeneration and the subsequent expression of amyloid precursor protein (APP), b-amyloid protein (b-AP), and apolipoprotein E (APO-E) in the selectively vulnerable CA1 region of the hippocampus. The increase in immunoreactivity is secondary to the postischemic degeneration of the CA1 neurons and is largely astrocyte-derived as evidenced by a simultaneous increase in glial fibrillary acidic protein (GFAP) staining. Oxygen radical-induced lipid peroxidation has been strongly suggested to play a role in postischemic neuronal damage and Alzheimer's disease. Recent literature suggests a possible link between early oxidative stress and APP overexpression. Therefore, the present investigation examined the effect of two novel brain-penetrating pyrrolopyrimidine lipid peroxidation inhibitors (PNU-101033E and PNU-104067F) on CA1 neurodegeneration and the subsequent increase in APP, b-AP, APO-E, and GFAP immunostaining at 4 days after a 5-minute episode of forebrain ischemia. Using an antibody for lipid peroxidation-derived malondialdehyde (MDA)-modified proteins, the authors also examined the effects of PNU-104067F on MDA immunostaining 2 days after ischemia, before completion of the neuronal loss. At 2 days, the authors also evaluated microglial activation using an antibody to surface major histocompatibility complex class II antigen expressed by activated microglia. Gerbils were treated at 30 mg/kg orally 30 minutes before the BCO and 2 hours after ischemia, followed by daily dosing for the next day (microglia and MDA) and the successive 3 days for APP, b-AP, APO-E, and GFAP immunostaining. APP and APO-E staining was significantly suppressed by 50% and 66%, respectively, with either compound. b-AP immunoreactivity was decreased 56% with both compounds, and GFAP expression was significantly decreased 53% (PNU-101033E) and 60.5% (PNU-104067F). There was a concomitant partial sparing of the CA1 hippocampal neurons by both PNU-101033E and PNU-104067F (P < .01) as determined by cresyl violet histochemistry. PNU-104067F significantly inhibited lipid peroxidation-derived MDA immunostaining and microglia activation (P < .05) at 48 hours after ischemia. Brain-penetrable lipid peroxidation inhibitors may provide attenuation of various glial response proteins after ischemic injury, probably secondary to neuronal protection.

Animals↗

PubMed1998

U74389G prevents vasospasm after subarachnoid hemorrhage in dogs.

OBJECTIVE: Oxygen-derived free radicals may contribute to vasospasm after the rupture of an intracranial aneurysm through direct vasoconstricting effects occurring within the arterial wall or, secondarily, by causing lipid peroxidation in the subarachnoid erythrocytes with secondary induction of vasoconstriction. U74389G is a potent inhibitor of lipid peroxidation and a scavenger of oxygen-derived free radicals. This study determined the relative contributions of oxygen-derived free radicals and lipid peroxidation to vasospasm in the double-hemorrhage dog model. METHODS: Sixteen dogs underwent baseline (Day 0) cerebral angiography and induction of subarachnoid hemorrhage by two injections of blood into the cisterna magna 2 days apart. They were randomized to receive drug vehicle (n=8) or U74389G (n=8, 3 mg/kg of body weight/d) intravenously. Drug administration and end point analysis were blinded. The end points were angiographic vasospasm, as assessed by comparison of angiograms obtained before and 7 days after subarachnoid hemorrhage, and the levels of malondialdehyde and salicylate hydroxylation products (dihydroxybenzoic acids) in cerebrospinal fluid and of malondialdehyde in subarachnoid blood clots and basilar arteries 7 days after hemorrhage. RESULTS: Comparisons within groups of Day 0 and Day 7 angiograms and between groups of angiograms obtained at Day 7, showed significant vasospasm in animals in the vehicle group (mean+/-standard error, 51%+/-4) but not in the U74389G group (25%+/-11, P < 0.05, unpaired t test). High-pressure liquid chromatographic assays of malondialdehyde and dihydroxybenzoic acids in cerebrospinal fluid, subarachnoid blood clots, and basilar arteries showed no significant differences between groups. CONCLUSION: The significant prevention of vasospasm by U74389G without change in levels of indicators of free radical reactions suggests that the effect of the drug is related to other processes occurring in the arterial wall and that cerebrospinal fluid levels of oxygen radicals and lipid peroxides are not useful markers of vasospasm.

Animals↗

PubMed1998

Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis.

Riluzole was tested in a dose-ranging study for preservation of motor function in a transgenic mouse model of familial ALS. The model is based on expression of mutant human Cu,Zn superoxide dismutase in mouse brain and spinal cord. In contrast with the human ALS trials, in the mouse model, riluzole significantly preserved motor function as assessed by nightly running in a wheel. The effect of riluzole on motor performance was greater earlier in disease than later, suggesting that riluzole may have benefit for "quality-of-life" measures in ALS. Treatment with riluzole was initiated earlier in the transgenic model than in the human ALS trials, which may account for the significantly better outcome.

Amyotrophic Lateral Sclerosis↗

PubMed1997

Immunocytochemical method for investigating in vivo neuronal oxygen radical-induced lipid peroxidation.

The investigation of oxygen radical-induced lipid peroxidative neuronal damage in the context of acute and chronic neurodegenerative disorders has been largely limited to the use of ex vivo analytical methodologies. These are often fraught with sensitivity or specificity problems, or they are indirect. Furthermore, none of the analytical methods allow precise anatomical identification of the cells that are undergoing peroxidative injury. This paper describes an immunocytochemical method for localization of central nervous system (CNS) lipid peroxidation (LP) that employs a rabbit-derived antibody raised against malondialdehyde (MDA)-modified rabbit serum albumin (RSA). MDA is a breakdown product of peroxidized membrane polyunsaturated fatty acids that avidly binds to cellular proteins. Using the anti-MDA-RSA, we herein illustrate increased MDA-derived immunostaining: (1) in the spinal cord of transgenic familial amyotrophic lateral sclerosis (ALS) mice; and (2) in the selectively vulnerable gerbil hippocampal CA1 region after a 5 min episode of forebrain ischemia and its relationship to the time course of neuronal degeneration.

Amyotrophic Lateral Sclerosis↗

PubMed1997

Neuroprotective effects of the GABA(A) receptor partial agonist U-101017 in 3-acetylpyridine-treated rats.

The neuroprotective effects of U-101017, [7-chloro-5-[cis-3,5-dimethylpiperazine)carbonyl]-imidazole[1,5a]quinoli ne-3-carboxylate], a GABA(A) receptor partial agonist, were investigated in 3-acetylpyridine (3-AP) treated Wistar rats. A significant (P < 0.01) reduction in both cGMP and ATP in the cerebellum was observed at 96 h after treatment with 3-AP (500 micromol/kg i.p.). Oral administration of U-101017 before and after treatment with 3-AP significantly attenuated 3-AP-induced decreases in cGMP and ATP, and this effect was dose related. Consistent with the neurochemical effect, U-101017 prevented 3-AP-induced loss of motor coordination. Treatment with U-101017 partially, but significantly (P < 0.01) prevented the loss of inferior olivary neurons. U-101017 had no significant effect on body temperature. Thus, hypothermia was not involved in neuroprotective effects of U-101017. Co-administration of flumazenil with each treatment of U-101017 blocked the neuroprotective effect of U-101017, indicating that it mediated neuroprotection via the benzodiazepine binding sites on the GABA(A) receptor complex. Delayed administration of U-101017 at various time intervals after treatment with 3-AP demonstrated a significant neuroprotective effect even at 8 h, suggesting that this drug has a wide therapeutic window.

Adenosine Triphosphate↗

PubMed1997

Neuroprotective effects of the dopamine agonists pramipexole and bromocriptine in 3-acetylpyridine-treated rats.

The neuroprotective effects of pramipexole, a dopamine agonist, were investigated in 3-acetylpyridine (3-AP)-treated Wistar rats. Bromocriptine was used as a reference compound to compare the results obtained with pramipexole. A significant reduction (P < 0.01) in cerebellar cGMP and ATP was observed 96 h after treatment with 3-AP (500 micromol/kg, i.p.). Both pramipexole and bromocriptine significantly attenuated 3-AP-induced reduction in cerebellar cGMP and ATP. Consistent with the neurochemical effect, both pramipexole and bromocriptine prevented 3-AP-induced loss of motor coordination. 3-Acetylpyridine produced a significant (P < 0.01) loss of neurons in the inferior olivary nucleus. Treatment with pramipexole and bromocriptine partially, but significantly (P < 0.01), prevented the loss of inferior olivary neurons. There was no reduction in the temperature of the animals, indicating that hypothermia was not responsible for neuroprotection.

Adenosine Triphosphate↗

PubMed1997

Neuroprotective effects of the novel brain-penetrating pyrrolopyrimidine antioxidants U-101033E and U-104067F against post-ischemic degeneration of nigrostriatal neurons.

A 10-min period of bilateral carotid occlusion (BCO)-induced forebrain ischemia in gerbils triggers a delayed retrograde degeneration of 35-40% of dopaminergic nigrostriatal (NS) neurons. The mechanism of the NS degeneration is believed to involve oxygen radical formation secondary to a postischemic increase in dopamine turnover (monoamine oxidase, MAO). If the oxygen radical increase is sufficiently severe, lipid peroxidative injury to the striatal NS terminals is followed by retrograde degeneration of the NS cell bodies. In the present study, we examined whether the novel brain-penetrating lipid antioxidant pyrrolopyrimidine, U-101033E, and its aromatized analog, U-104067F, could attenuate dopaminergic neurodegeneration in this model. Male Mongolian gerbils were dosed with U-101033E (1.5, 5, or 15 mg/kg, by mouth, twice daily) or U-104067F (5 or 15 mg/kg, by mouth, twice daily) for 27 days beginning on the day of the 10-min ischemic insult. Preservation of NS neurons was assessed by tyrosine hydroxylase immunohistochemistry at 28 days. In vehicle (40% hydroxypropyl-beta-cyclodextrin)-treated animals, there was a 42% loss of NS neurons. In contrast, gerbils that received 5 or 15 mg/kg U-101033E twice daily had only a 23% or 28% loss of NS neurons, respectively (P < 0.002 vs. vehicle). U-104067F showed little effect at sparing neurons at the 10 mg/kg dose, but did significantly attenuate neuronal loss to only 20% at the 30 mg/kg dose (P < 0.01 vs. vehicle). The results show that both the pyrrolopyrimidines (U-101033E and U-104067F) significantly attenuate the postischemic loss of NS dopaminergic neurons and further support the involvement of a dopamine metabolism-derived, oxygen radical-induced lipid peroxidative mechanism.

Animals↗

PubMed1997

Neuroprotective properties of the benzodiazepine receptor, partial agonist PNU-101017 in the gerbil forebrain ischemia model.

PNU-101017 is a novel, imidazoquinoline amide and benzodiazepine receptor partial agonist that has high affinity for the GABAA receptor subtypes containing the alpha 1 and alpha 3 or alpha 5 subunits. At each of these receptors, the compound is a partial agonist with approximately 50% of the intrinsic activity of the full agonist diazepam. In view of the previously demonstrated anti-ischemic effects of some GABA agonists, the purpose of this study was to determine the ability of PNU-101017 to salvage selectively vulnerable neuronal populations in the gerbil forebrain ischemia model. In an initial set of experiments, male gerbils were pretreated 30 minutes before ischemia induction (5 minutes) with PNU-101017 (3, 10, or 30 mg/kg intraperitoneally) and again 2 hours after reperfusion. In vehicle (0.05 N HC1)-treated gerbils, the loss of hippocampal CA1 neurons at 5 days was 80%. PNU-101017 was shown to produce a dose-related increase in CA1 neuronal survival; at either 10 or 30 mg/kg, the loss of CA1 neurons was only 21% (P < 0.005 versus vehicle). A second experiment, examined the therapeutic window for PNU-101017 using the dose level of 30 mg/kg intraperitoneally. Administration of the first of two doses (2 hours apart) at the time of reperfusion resulted in an identical decrease in CA1 damage at 5 days to that seen with preischemic treatment (P < 0.003 versus vehicle). Even with a delay of the initial dosing until 4 hours after reperfusion, PNU-101017 reduced CA1 neuronal loss to only 32% (P < 0.01 versus vehicle). In a third experiment in which the duration of the ischemic insult was increased to 10 minutes and the brains were not analyzed until 28 days after ischemia, daily PNU-101017 dosing for the full 28 days still significantly preserved CA1 neurons, although less effectively than in the milder 5 minute-ischemia model. The loss of dopaminergic nigrostriatal neurons was also reduced. The neuroprotective effect of PNU-101017 was not associated with any overt CNS depression and it did not correlate with hypothermia. This benzodiazepine-receptor partial agonist may have potential for the treatment of global cerebral ischemia.

Amides↗

PubMed1997

Brain attack. Acute therapeutic interventions. Free radical scavengers and antioxidants.

Evidence suggesting a role of oxygen radical-induced lipid peroxidation in global and focal ischemic brain damage is reviewed, and the potential for treatment of these conditions with antioxidant compounds is highlighted. This article also presents a basis for appreciating the pharmacologic mechanisms by which oxygen radical damage can be inhibited.

Animals↗

PubMed1997

Pyrrolopyrimidines: novel brain-penetrating antioxidants with neuroprotective activity in brain injury and ischemia models.

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.

Animals↗

PubMed1996

Neuroprotective effects of the dopamine D2/D3 agonist pramipexole against postischemic or methamphetamine-induced degeneration of nigrostriatal neurons.

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.

Animals↗

PubMed1996

Treatment of mice with methamphetamine produces cell loss in the substantia nigra.

Studies were conducted to determine if treatment of mice with methamphetamine (METH) would produce a loss of dopaminergic cells in the substantia nigra. The number of TH+/Nissl-stained was significantly decreased in both Swiss-Webster (S-W) and C57bl mice (approx. cell loss of 40% and 45%, respectively) 5-8 days after treatment with METH. In these same mice there was a corresponding decrease in neostriatal dopamine (DA) content (90% and 92%, respectively). In parallel studies, treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produced similar neuropathological effects. The finding that nigral cell loss occurs after METH treatment indicates that the METH-treated mouse may be a very relevant model of Parkinson's disease (PD).

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1996

Inhibition of lipid peroxidation attenuates axotomy-induced apoptotic degeneration of facial motor neurons in neonatal rats.

The purpose of this study was to investigate the role of oxygen radical-induced lipid peroxidative mechanisms in trophic deprivation-induced apoptotic motor neuronal degeneration by testing the ability of the 21-aminosteroid lipid peroxidation inhibitor tirilazad mesylate (U-74006F) to attenuate the retrograde degeneration of facial motor neurons following axotomy in 14-day-old rat pups. On day 0, the right facial nerve of each rat was transected at its point of exit from the stylomastoid foramen. Pups were treated orally with either 10 or 30 mg/kg U-74006F or cyclodextrin vehicle 10 min before axotomy, and post-treated once a day from days 1 to 6, and then once every other day from days 8 to 21. The rats were sacrificed 3 weeks post-transection and the surviving motor neurons, identified through choline acetyltransferase immunocytochemistry, were counted in three regions (planes) in the facial nucleus. In vehicle-treated rats, 56.2% (region A), 50.6% (region B), and 57.4% (region C) of the motor neurons in the ipsilateral facial nucleus survived 21 days following facial nerve axotomy in comparison to the non-axotomized contralateral nucleus (P < 0.0001). Treatment with 10 mg/kg U-74006F significantly enhanced motor neuron survival in regions B and C to 72.8% (P < 0.01) and 66.7% (P < 0.02%), respectively. The 30 mg/kg dose level also increased survival rates to 64.2% (P < 0.02) and 67.9% (P < 0.01), respectively. A second experiment demonstrated that oral dosing with U-74006F (30 mg/kg), when limited to the first 5 days after axotomy, also significantly blunted retrograde degeneration measured at 21 days post-axotomy. The efficacy of the lipid peroxidation inhibitor U-74006F in protecting a portion of the facial motor neuron pool from post-axotomy degeneration suggests that lipid peroxidation may play a mechanistic role in trophic deprivation-induced apoptotic neuronal death.

Animals↗

PubMed1996

Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis.

Familial amyotrophic lateral sclerosis (FALS) has been linked in some families to dominant mutations of the SOD1 gene encoding Cu,Zn superoxide dismutase (Cu,ZnSOD). We have used a transgenic model of FALS based on expression of mutant human Cu,ZnSOD to explore the etiology and therapy of the genetic disease. Expression of mutant, but not wild-type, human Cu,ZnSOD in mice places the brain and spinal cord under oxidative stress. This causes depletion of vitamin E, rather than the typical age-dependent increase in vitamin E content as occurs in nontransgenic mice and in mice expressing wild-type human Cu,ZnSOD. Dietary supplementation with vitamin E delays onset of clinical disease and slows progression in the transgenic model but does not prolong survival. In contrast, two putative inhibitors of the glutamatergic system, riluzole and gabapentin, prolong survival. However, riluzole did not delay disease onset. Thus, there was clear separation of effects on onset, progression, and survival by the three therapeutics tested. This suggests the hypothesis that oxidative damage produced by the expression of mutant Cu,ZnSOD causes slow or weak excitotoxicity that can be inhibited in part by alerting glutamate release or biosynthesis presynaptically.

Acetates↗

PubMed1996

Neuroprotective effects of the pyrrolopyrimidine U-104067F in 3-acetylpyridine-treated rats.

The neuroprotective effects of U-104067F[(9-(2-morpholinyl)ethyl) 2,4-di-l-pyrrolidinyl-9H-pyrimidino (4,5-b)(4,5indole monohydrochloride hydrate], a pyrrolopyrimidine antioxidant, were investigated in 3-acetylpyridine (3-AP)-treated Wistar rats. A significant (P < 0.01) reduction in cerebellar cGMP and ATP was observed at 96 h after treatment with 3-AP (500 micromol/kg ip). Oral administration of U-104067F significantly attenuated 3-AP-induced reductions in cGMP and ATP, and this effect was dose related. Consistent with the neurochemical effect, U-104067F prevented 3-AP-induced loss of motor coordination. 3-Acetylpyridine produced a significant (P < 0.01) loss of neurons in the inferior olivary nucleus. Treatment with U-104067F partially, but significantly (P < 0.01), prevented the loss of inferior olivary neurons. The physiological and neurochemical parameters were maintained within normal limits by U-104067F in 3-AP-treated rats despite only partial preservation of inferior olivary neurons.

Adenosine Triphosphate↗

PubMed1996

Two novel pyrrolopyrimidine lipid peroxidation inhibitors U-101033E and U-104067F protect facial motor neurons following neonatal axotomy.

Recent reports suggest that oxygen radical-induced lipid peroxidation plays a role in the retrograde degeneration of motor neurons following facial nerve axotomy in the neonatal rat. The purpose of the present study was to explore this notion further by testing the neuroprotective properties of two novel brain-penetrating, lipid peroxidation inhibitors, U-101033E and U-104067F, in this model of neuronal degeneration. In Experiment 1, 14-day-old rats were pretreated with 3, 10, or 30 mg/kg U-101033E (po) 10 min before right facial nerve axotomy (Day 0) and then posttreated once a day from Day 1 to Day 6, and once every other day from Day 8 to Day 21. Rats were sacrificed 21 days postaxotomy and surviving cholinergic cell bodies were identified using choline acetyltransferase immunocytochemistry. Both 10 and 30 mg/kg U-101033E significantly enhanced motor neuron survival, with survival rates of 65.9-88.9% being noted in comparison to 51.7-62% survival in vehicle controls (P < or = 0.05). Experiment 2 demonstrated a significant neuroprotective effect of 10 and 30 mg/kg U-104067F using the same dosing schedule. Experiment 3 was designed to test whether shorter periods of drug exposure (e.g., 5 or 7 days) would be sufficient to preserve motor neurons in rats treated with 10 mg/kg U-101033E. The results suggested that as little as 5 days of drug treatment is sufficient to enhance motor neuron survival. Finally, Experiment 4 demonstrated an 18-19% increase in motor neuron survival in rats treated with 10 and 30 mg/kg U-104067F for 5 consecutive days postaxotomy. Taken together, the attenuation of motor neuron degeneration by the two pyrrolopyrimidine lipid peroxidation inhibitors, U-101033E and U-104067F, lends support to the notion that lipid peroxidation contributes to the pathogenesis of axotomy-induced neurodegeneration.

Animals↗