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Biomedical subjects

A I Faden

Publications and source records attributed to A I Faden.

At least 19 recordsLinked to original sources
PubMed1992

N-methyl-D-aspartate (NMDA) and opioid receptors mediate dynorphin-induced spinal cord injury: behavioral and histological studies.

Both N-methyl-D-aspartate (NMDA) and opioid receptors have been implicated in the pathophysiology of traumatic spinal cord injury and dynorphin-induced paralysis. The present studies compared the effects of the non-competitive NMDA antagonist dextrorphan (Dex) and the kappa-selective opioid antagonist nor-binaltorphimine (nor-BNI) on the acute motor deficits and chronic neuropathological alterations caused by intrathecally administered dynorphin A-(1-17) (Dyn A). Infusion of Dyn A into the rat lower thoracic spinal subarachnoid space produced acute, reversible hindlimb paresis. Histological evaluations of spinal cord sections from these animals at 2 weeks post-infusion revealed ventral grey matter necrosis, neuronal loss and gliosis as well as axonal loss in adjacent white matter; however, there was minimal alteration in serotonin immunocytochemistry caudal to the injury zone. Dex or non-BNI pretreatment each significantly (P less than 0.05) reduced, and to a similar degree, the acute motor deficits and certain histological changes associated with Dyn A administration. These findings further support the hypothesis that dynorphin-induced spinal cord injury involves both NMDA receptors and opioid receptors.

Animals↗
PubMed1992

Pretreatment with NMDA antagonists limits release of excitatory amino acids following traumatic brain injury.

After central nervous system (CNS) trauma, there are marked elevations in the extracellular levels of excitatory amino acids (EAA), which are believed to contribute to delayed tissue damage. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists reduces injury severity after brain or spinal cord trauma, presumably by blocking the postsynaptic NMDA receptor. In the present studies, levels of extracellular amino acids were monitored by microdialysis during, and after, a moderately severe fluid-percussion brain injury to rats. Pretreatment (15 min prior to injury) with the non-competitive NMDA antagonist dextrorphan or the competitive NMDA antagonist CGS 19755 significantly attenuated the post-traumatic increase in extracellular glutamate. Pretreatment with dextrorphan attenuated the post-traumatic increase in extracellular levels of aspartate; although these differences did not reach significance when examined as absolute values, they were significant when analyzed as percent increase over pre-trauma baseline levels. These results are consistent with recent experiments and suggest that NMDA antagonists may limit the release of glutamate and aspartate after trauma through a presynaptic mechanism.

Amino Acids↗
PubMed1992

Alcohol exacerbates behavioral and neurochemical effects of rat spinal cord trauma.

Acute alcohol intoxication may exacerbate the consequences of central nervous system trauma, although the mechanism is uncertain. Effects of acute ethanol administration on behavioral and neurochemical changes were examined in rats after traumatic spinal cord injury. Survival rates were reduced and posttraumatic neurologic function worsened in ethanol-treated as compared with saline-treated controls. Ethanol-treated rats had significantly lower tissue levels of excitatory amino acids and higher levels of free fatty acids, thromboxane, and lactic acid than did controls. Tissue magnesium concentration was significantly reduced by trauma and recovered more slowly in ethanol-treated rats. Enhanced phospholipid hydrolysis with free fatty acid and thromboxane accumulation, increased release of excitatory amino acids, and decreased tissue magnesium levels may each serve to worsen secondary tissue damage and diminish neurologic recovery after spinal cord injury associated with acute alcohol intoxication.

Amino Acids↗
PubMed1992

Pharmacological strategies in CNS trauma.

Delayed biochemical changes play an important role in tissue damage resulting from traumatic injuries to the central nervous system. Identification of such 'secondary' injury factors has led to the development of various pharmacological strategies aimed at limiting this progressive tissue destruction. In this review, Alan Faden and Steven Salzman discuss the pharmacological approaches that have the most experimental support. These include corticosteroids, antioxidants and free-radical scavengers, modulators of arachidonate metabolism, gangliosides, monoamine modulators, opioid receptor antagonists, TRH and its analogs, NMDA receptor antagonists, Ca2+ channel antagonists and platelet-activating factor antagonists.

Animals↗
PubMed1992

Effect of dichloroacetate on recovery of brain lactate, phosphorus energy metabolites, and glutamate during reperfusion after complete cerebral ischemia in rats.

The effects of dichloroacetate (DCA) on brain lactate, intracellular pH (pHi), phosphocreatine (PCr), and ATP during 60 min of complete cerebral ischemia and 2 h of reperfusion were investigated in rats by in vivo 1H and 31P magnetic resonance spectroscopy; brain lactate, water content, cations, and amino acids were measured in vitro after reperfusion. DCA, 100 mg/kg, or saline was infused before or immediately after the ischemic period. Preischemic treatment with DCA did not affect brain lactate or pHi during ischemia, but reduced lactate and increased pHi after 30 min of reperfusion (p < 0.05 vs. controls) and facilitated the recovery of PCr and ATP during reperfusion. Postischemic DCA treatment also reduced brain lactate and increased pHi during reperfusion compared with controls (p < 0.05), but had little effect on PCr, ATP, or Pi during reperfusion. After 30 min of reperfusion, serum lactate was 67% lower in the postischemic DCA group than in controls (p < 0.05). The brain lactate level in vitro was 46% lower in the postischemic DCA group than in controls (p < 0.05). DCA did not affect water content or cation concentrations in either group, but it increased brain glutamate by 40% in the preischemic treatment group (p < 0.05). The potential therapeutic effects of DCA on brain injury after complete ischemia may be mediated by reduced excitotoxin release related to decreased lactic acidosis during reperfusion.

Adenosine Triphosphate↗
PubMed1992

Effects of hyperglycemia on the time course of changes in energy metabolism and pH during global cerebral ischemia and reperfusion in rats: correlation of 1H and 31P NMR spectroscopy with fatty acid and excitatory amino acid levels.

The effects of hyperglycemia on the time course of changes in cerebral energy metabolite concentrations and intracellular pH were measured by nuclear magnetic resonance (NMR) spectroscopy in rats subjected to temporary complete brain ischemia. Interleaved 31P and 1H NMR spectra were obtained every 5 min before, during, and for 2 h after a 30-min bilateral carotid occlusion preceded by permanent occlusion of the basilar artery. The findings were compared with free fatty acid and excitatory amino acid levels as well as with cations and water content in funnel-frozen brain specimens. One hour before occlusion, nine rats received 50% glucose (12 ml/kg i.p.) and five received 7% saline (12 ml/kg i.p.). Before ischemia, there were no differences in cerebral metabolite levels or pH between hyperglycemic rats and controls. During the carotid occlusion, the lactate/N-acetylaspartate (Lac/NAA) peak ratio was higher (0.73-1.48 vs. 0.56-0.82; p less than 0.05) and pH was lower (less than 6.0 vs. 6.45 +/- 0.05; p less than 0.05) in the hyperglycemic rats than in the controls. Phosphocreatine and adenosine triphosphate were totally depleted in both groups. Within 5-15 min after the onset of reperfusion, the Lac/NAA peak ratio increased further in all rats; however, only in extremely hyperglycemic rats (serum glucose greater than 960 mg/dl) did the lactic acidosis progress rather than recover later during reperfusion. Total free fatty acid and excitatory amino acid levels, but not cation concentration or water content, in brain correlated with serum glucose levels during and after ischemia and with NMR findings after 2 h of reperfusion. Although profound hyperglycemia (serum glucose of 970-1,650 mg/dl) appears to be associated with progression of anaerobic glycolysis and failure of cerebral energy metabolism to recover after temporary complete brain ischemia and with postischemic excitotoxic and lipolytic reactions thought to participate in delayed cellular injury, severe hyperglycemia (490-720 mg/dl) was associated with recovery of energy metabolism.

Acidosis, Lactic↗
PubMed1992

Platelet-activating factor antagonists limit glycine changes and behavioral deficits after brain trauma.

Tissue damage after traumatic brain injury (TBI) results in part from delayed biochemical changes initiated by the insult. Platelet-activating factor (PAF) is an alkylphospholipid that has been implicated in tissue damage after cerebral ischemia. PAF is toxic to certain neuronal cell lines in culture, reduces cerebral blood flow, alters the blood-brain barrier, and can enhance phospholipid hydrolysis. The recent development of receptor antagonists to PAF permits examination of its possible role in delayed tissue injury after neurotrauma. Treatment with the PAF receptor antagonists BN 52021 and WEB 2170 before injury significantly enhanced neurological recovery after fluid percussion-induced TBI in rats. Pretreatment with WEB 2170 also significantly limited alterations in tissue water content and tissue glycine levels after trauma, and reduced posttraumatic levels of extracellular glycine in ipsilateral hippocampus. These findings implicate PAF in the pathophysiology of TBI, through actions at PAF receptors. A possible role for glycine in this process is suggested.

Animals↗
PubMed1992

Dynorphin increases extracellular levels of excitatory amino acids in the brain through a non-opioid mechanism.

Administration of dynorphin A-(1-17) (Dyn 1-17), through a microdialysis probe stereotaxically placed into rat hippocampus, caused marked increases in the extracellular levels of glutamate and aspartate. The degree and duration of elevation of these excitatory amino acids (EAA) induced by Dyn 1-17 were dose dependent but were not modified by the centrally active opioid receptor antagonist nalmefene. At comparable doses, Dyn 2-17, which is inactive at the opioid receptor, produced similar alterations in EAA as Dyn 1-17, whereas Dyn 1-8 caused significantly smaller changes of glutamate. Dynorphin and EAAs have each been implicated as pathophysiological factors in brain or spinal cord injuries, with dynorphin's actions shown to involve both opioid and non-opioid components. The present observations indicate a direct potential linkage between dynorphin and excitotoxin mechanisms of CNS injury and provide further support for the concept that dynorphin's pathophysiologic effects may include non-opioid actions of this peptide.

Alanine↗
PubMed1992

Platelet-activating factor reduces spinal cord blood flow and causes behavioral deficits after intrathecal administration in rats through a specific receptor mechanism.

Platelet-activating factor (PAF) is a phospholipid that has been implicated in the pathophysiology of delayed tissue damage after various forms of brain injury including ischemia, hypoxia and trauma. To examine its effects in the spinal cord, PAF was administered intrathecally to rats. PAF caused dose-dependent (30-100 nmol) decreases in spinal cord blood flow, in motor function or in survival. These actions were not reproduced by the biologically inactive precursor lyso-PAF or the enantiomer of this alkyl-phospholipid, which is not active at PAF receptors. PAF-induced changes were blocked completely by the selective receptor antagonist WEB 2170. Together, these findings demonstrate that PAF can alter spinal cord blood flow and motor function through a specific receptor mechanism, suggesting that this phospholipid may play a role in secondary tissue damage after spinal cord injury.

Animals↗
PubMed1991

kappa-Opioid antagonist improves cellular bioenergetics and recovery after traumatic brain injury.

Treatment with opioid receptor antagonists improves outcome after experimental brain trauma, although the mechanisms underlying the protective actions of these compounds remain speculative. We have proposed that endogenous opioids contribute to the pathophysiology of traumatic brain injury through actions at kappa-opioid receptors, possibly by affecting cellular bioenergetic state. In the present study, the effects of the kappa-selective opioid-receptor antagonist nor-binaltorphimine (nor-BNI) were examined after fluid percussion brain injury in rats. Metabolic changes were evaluated by 31P magnetic resonance spectroscopy; the same animals were subsequently followed over 2 wk to evaluate neurological recovery. Nor-BNI, administered intravenously as a 10 or 20 mg/kg bolus at 30 min after injury, significantly improved neurological outcome at 2 wk posttrauma compared with controls. Animals treated with nor-BNI showed significantly greater recovery of intracellular free magnesium concentrations and cytosolic phosphorylation potentials during the first 4 h after injury compared with saline-treated controls. The improvement in cytosolic phosphorylation potential was significantly correlated to neurological outcome. These data support the hypothesis that kappa-opioid receptors mediate pathophysiological changes after traumatic brain injury and that the beneficial effects of opioid-receptor antagonist may result from improvement of posttraumatic cellular bioenergetics.

Animals↗
PubMed1990

Blockade of the glycine modulatory site of NMDA receptors modifies dynorphin-induced behavioral effects.

Intrathecal (i.t.) administration of the opioid dynorphin causes neurological dysfunction and tissue damage. It has been suggested that these effects of dynorphin may be mediated, in part, by N-methyl-D-aspartate (NMDA) receptors. In the present studies, recently developed compounds that block the glycine potentiation site of the NMDA receptor (Gly-NMDA site), including the competitive antagonist 5-fluoro-indole-2-carboxylic acid and the non-competitive antagonist 7-chlorokynurenic acid, prevented the neurologic deficits and mortality caused by i.t. dynorphin A(1-17). These findings are consistent with the hypothesis that dynorphin-induced neurological dysfunction involves activation of NMDA receptors. Moreover, blockade of the Gly-NMDA site may provide an alternative to blockade of the glutamate binding site or NMDA receptor ion channel as an in vivo pharmacological strategy to treat conditions previously associated with excitotoxin mediated tissue injury.

Animals↗
PubMed1990

Changes in extracellular amino acid neurotransmitters produced by focal cerebral ischemia.

Excitatory amino acids (EAAs) have been implicated in the pathophysiology of cellular injury after brain ischemia. Changes in extracellular levels of amino acids in rat cerebral cortex after permanent proximal middle cerebral artery (MCA) occlusion were examined using microdialysis. Significant increases were found in dialysate concentrations of glutamate, aspartate and gamma-aminobutyric acid (GABA) from the ischemic cortex during the first 90 min after MCA occlusion compared to pre-ischemic concentrations and contralateral hemispheric controls. Total tissue levels of these amino acids in the infarcted hemisphere 90 min after onset of ischemia were not different from the contralateral hemisphere. These results are consistent with the hypothesis that the release of EAAs may contribute to tissue damage in focal cerebral ischemia.

Amino Acids↗
PubMed1990

Competitive and non-competitive NMDA antagonists limit dynorphin A-induced rat hindlimb paralysis.

It has been proposed that the endogenous opioid dynorphin A (Dyn A) contributes to the pathogenesis of posttraumatic spinal cord injury (SCI). Dyn A-related peptides given intrathecally (i.t.) produce hindlimb paralysis. These include Dyn A(1-17), Dyn A(1-13), Dyn A(2-17), and Dyn A(3-13). Because Dyn A(2-17) and Dyn A(3-13) are inactive at opiate receptors, Dyn A-induced paralysis may include a non-opioid component. Recently, it has been reported that competitive N-methyl-D-aspartate (NMDA) antagonists block the loss of tail-flick reflex caused by i.t. administration of Dyn A(1-13). In the present studies we examined whether competitive [(4-[3-phosphonopropyl]-2-piperazine-carboxylic acid (CPP)] or non-competitive (dextrorphan) NMDA antagonists could attenuate paralysis induced by Dyn A(1-17) or Dyn A(2-17). CPP or dextrorphan each significantly attenuated the neurologic dysfunction and mortality associated with Dyn A(1-17) administration. In addition, CPP and dextrorphan significantly reduced the neurologic dysfunction caused by Dyn A(2-17)(all P less than 0.05). From these data we suggest that the non-opioid component of Dyn A-induced paralysis is mediated in part by the NMDA receptor.

Animals↗
PubMed1990

Effects of competitive and non-competitive NMDA receptor antagonists in spinal cord injury.

The potential role of N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of spinal cord injury was examined in rats by comparing the effects of the non-competitive NMDA antagonist dextrorphan and the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) on the behavioral and anatomical consequences of impact trauma to the spinal cord. Treatment with either dextrorphan or CPP, administered intrathecally 15 min after trauma, significantly improved chronic (4 weeks) behavioral recovery. Treatment with CPP, but not dextrorphan, limited the decline in serotonin below the injury zone, as shown by both immunocytochemistry and high performance liquid chromatography. Beneficial effects of CPP were dose-dependent. Dextrorphan treatment also improved behavioral outcome when the drug was administered intravenously. These studies implicate NMDA receptor-mediated excitotoxins in tissue damage following spinal cord trauma and suggest that NMDA antagonists may be of value in the treatment of acute, clinical spinal cord injury.

Amino Acids↗
PubMed1990

Decreases in tissue levels of ubiquinol-9 and -10, ascorbate and alpha-tocopherol following spinal cord impact trauma in rats.

Generation of free radicals and subsequent lipid peroxidation have been proposed to contribute to delayed tissue damage following traumatic spinal cord injury (SCI). Ubiquinols (reduced coenzyme Q), ascorbate (vitamin C), and alpha-tocopherol (vitamin E) are endogenous antioxidants; decreases in tissue levels of these compounds may, therefore, reflect ongoing oxidative reactions. In the present studies, alterations in tissue levels of ubiquinol-9 and -10, ascorbate, and alpha-tocopherol were examined after SCI of varying severity in the rat. Levels of alpha-tocopherol did not change significantly after injury. Ascorbate and ubiquinol levels were decreased after trauma. Changes in tissue levels of ubiquinol, but not ascorbate reflected the degree of trauma. Thus, ubiquinol levels may provide a useful marker of the oxidative component of the secondary injury response.

Animals↗
PubMed1990

Comparison of the neuroprotective effects of the N-methyl-D-aspartate antagonist MK-801 and the opiate-receptor antagonist nalmefene in experimental spinal cord ischemia.

Both N-methyl-D-aspartate (NMDA)-receptor antagonists and opiate-receptor antagonists have been shown to limit tissue damage after ischemic central nervous system injury. We compared the neuroprotective effects of the noncompetitive NMDA-receptor antagonist MK-801 and the opiate-receptor antagonist nalmefene in a model of global spinal cord ischemia and reperfusion in unanesthetized rabbits. MK-801 (1 mg/kg) or nalmefene (0.1 mg/kg) was administered intravenously 5 minutes after reperfusion. MK-801 treatment and nalmefene treatment each significantly improved the neurologic and histologic outcome compared with saline controls. Differences in these outcome measures between MK-801 treatment and nalmefene treatment did not reach statistical significance. Our results are consistent with the hypothesis that multiple factors, including endogenous opioids and excitatory amino acids, contribute to the secondary tissue injury after central nervous system ischemia. These data also provide further evidence that therapeutic interventions with opiate-receptor antagonists or NMDA antagonists may be beneficial in limiting neurologic dysfunction after ischemic brain or spinal cord injury.

Animals↗
PubMed1990

Opioid and nonopioid mechanisms may contribute to dynorphin's pathophysiological actions in spinal cord injury.

It has been suggested that the opioid dynorphin, an endogenous agonist for kappa-opiate receptors, contributes to secondary tissue damage after spinal cord injury. To evaluate this hypothesis further, effects of intrathecally administered dynorphin (Dyn) A-(1-17), dynorphin antiserum, or the kappa-selective opiate antagonist nor-binaltorphimine (nor-BNI) were studied in rats subjected to standardized impact trauma to the thoracic spinal cord. Effects of intrathecal Dyn A-(1-17) were also compared to those of Dyn A-(2-17), which is inactive at opiate receptors, in uninjured and injured animals. Both Dyn A-(1-17) and Dyn A-(2-17) produced motor dysfunction in uninjured rats, but Dyn A-(1-17) was approximately 2.5 times more potent. At lower doses of Dyn A-(1-17), paraparesis was markedly attenuated by nor-BNI; nor-BNI was less effective at higher doses of Dyn A-(1-17) and did not modify the motor dysfunction produced by Dyn A-(2-17). Treatment with dynorphin antiserum significantly improved outcome after trauma as compared to control treatment with normal rabbit serum or leucine-enkephalin antiserum. Dyn A-(1-17), but not Dyn A-(2-17) at similar doses, exacerbated neurological dysfunction after spinal cord injury. Pretreatment with nor-BNI attenuated neurological dysfunction after traumatic spinal cord injury to a similar degree in rats administered saline or Dyn A-(1-17). These observations support the hypothesis that dynorphin contributes to certain pathophysiological changes after traumatic spinal cord injury through both opiate-receptor (kappa-receptor)-mediated and nonopioid mechanisms.

Animals↗