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Paul L Wood

Publications and source records attributed to Paul L Wood.

10 recordsLinked to original sources
PubMed2006

Aldehyde load in ischemia-reperfusion brain injury: neuroprotection by neutralization of reactive aldehydes with phenelzine.

In ongoing studies of the neuroprotective properties of monoamine oxidase inhibitors, we found that phenelzine provided robust neuroprotection in the gerbil model of transient forebrain ischemia, with drug administration delayed up to 3 h post reperfusion. Since ischemia-reperfusion brain injury is associated with large increases in the concentrations of reactive aldehydes in the penumbra area, we investigated if the hydrazine function of phenelzine was capable of sequestering reactive aldehydes. Both aminoaldehydes and acrolein are generated from the metabolism of polyamines to putrescine by polyamine oxidase. These toxic aldehydes in turn compromise mitochondrial and lysosomal integrity and initiate apoptosis and necrosis. Previous studies have demonstrated that pharmacological neutralization of reactive aldehydes via the formation of thioacetal derivatives results in significant neuroprotection in ischemia-reperfusion injury, in both focal and global ischemia models. In our studies of acrolein and 3-aminopropanal toxicity, using an immortalized retinal cell line, we found that aldehyde sequestration with phenelzine was neuroprotective. The neuroprotection observed with phenelzine is in agreement with previous studies of aldehyde sequestering agents in the treatment of ischemia-reperfusion brain injury and supports the concept that "aldehyde load" is a major factor in the delayed cell losses of the ischemic penumbra.

Acrolein↗
PubMed2006

Neurotoxicity of reactive aldehydes: the concept of "aldehyde load" as demonstrated by neuroprotection with hydroxylamines.

The concept of "oxidative stress" has become a mainstay in the field of neurodegeneration but has failed to differentiate critical events from epiphenomena and sequalae. Furthermore, the translation of current concepts of neurodegenerative mechanisms into effective therapeutics for neurodegenerative diseases has been meager and disappointing. A corollary of current concepts of "oxidative stress" is that of "aldehyde load". This relates to the production of reactive aldehydes that covalently modify proteins, nucleic acids, lipids and carbohydrates and activate apoptotic pathways. However, reactive aldehydes can also be generated by mechanisms other than "oxidative stress". We therefore hypothesized that agents that can chemically neutralize reactive aldehydes should demonstrate superior neuroprotective actions to those of free radical scavengers. To this end, we evaluated hydroxylamines as aldehyde-trapping agents in an in vitro model of neurodegeneration induced by the reactive aldehyde, 3-aminopropanal (3-AP), a product of polyamine oxidase metabolism of spermine and spermidine. In this model, the hydroxylamines N-benzylhydroxylamine, cyclohexylhydroxylamine and t-butylhydroxylamine were shown to protect, in a concentration-dependent manner, against 3-AP neurotoxicity. Additionally, a therapeutic window of 3 h was demonstrated for delayed administration of the hydroxylamines. In contrast, the free radical scavengers TEMPO and TEMPONE and the anti-oxidant ascorbic acid were ineffective in this model. Extending these tissue culture findings in vivo, we examined the actions of N-benzylhydroxylamine in the trimethyltin (TMT) rat model of hippocampal CA3 neurodegeneration. This model involves augmented polyamine metabolism resulting in the generation of reactive aldehydes that compromise mitochondrial integrity. In the rat TMT model, NBHA (50 mg/kg, sc, daily) provided 100% protection against neurodegeneration, as reflected by measurements of KCl-evoked glutamate release from hippocampal brain slices and septal high affinity glutamate uptake. In contrast, ascorbic acid (100 mg/kg, sc, daily) failed to protect CA3 neurons from TMT toxicity. In summary, our data support further evaluation of the concept of "aldehyde load" in neurodegeneration and the potential clinical investigation of agents that are effective traps for reactive aldehydes.

Aldehydes↗
PubMed2006

Neurochemical analysis of amino acids, polyamines and carboxylic acids: GC-MS quantitation of tBDMS derivatives using ammonia positive chemical ionization.

The GC-MS quantitation of a large number of neurochemicals utilizing a single derivatization step is not common but is provided by the reagent N-(tert-butyldimethylsilyl)-N-methyltrifluro-acetamide (MTBSTFA). Previous workers have utilized this derivative for GC-MS analyses of amino acids, carboxylic acids and urea with electron impact (EI) and with positive chemical ionization (PCI; methane as reagent gas). However, these conditions yield significant fragmentation, decreasing sensitivity and in some cases reducing specificity for quantitation with selected ion monitoring (SIM). Additionally, the majority of studies have used a single internal standard to quantitate many compounds. In this study we demonstrate that using isotopic dilution combined with ammonia as the reagent gas for PCI analyses, results in high precision and sensitivity in analyzing complex neurochemical mixes. We also demonstrate for the first time the utility of this derivative for the analysis of brain polyamines and the dipeptide cysteinyl glycine. In the case of ammonia as the reagent gas, all amino acids, polyamines and urea yielded strong [MH](+) ions with little or no fragmentation. In the case of carboxylic acids, [M+18](+) ions predominated but [MH](+) ions were also noted. This approach was used to analyze superfusates from hippocampal brain slices and brain tissue extracts from brain lesion studies. The advantages of this methodology include: (i) simple sample preparation; (ii) a single derivatization step; (iii) direct GC-MS analysis of the reaction mix; (iv) high precision as a result of isotopic dilution analyses; (v) high sensitivity and specificity as a result of strong [MH](+) ions with ammonia reagent gas; (vi) no hydrolysis of glutamine to glutamate or asparagine to aspartate; and (vii) applicability to a wide range of neurochemicals.

Acetamides↗
PubMed2005

GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator.

We previously created a monoclonal antibody (MAb), B6B21, that acts as a partial agonist at the glycine site of the N-methyl-d-aspartate (NMDA) receptor [Moskal, J.R., Schaffner, A.E., 1986. Monoclonal antibodies to the dentate gyrus: immunocytochemical characterization and flow cytometric analysis of hippocampal neurons bearing a unique cell-surface antigen. J. Neurosci. 6, 2045-2053.]. The hypervariable region of the light chain of B6B21 was cloned and sequenced. Peptides were then synthesized based on this sequence information and screened using rat hippocampal membrane preparations to measure [(3)H]MK-801 binding in the presence of 7-chlorokynurenic acid, a glycine site-specific competitive inhibitor of NMDA receptor [Moskal, J.R., Yamamoto, H., Colley, P.A., 2001. The use of antibody engineering to create novel drugs that target N-methyl-d-aspartate receptors. Curr. Drug Targets 2, 331-345.]. Peptides that were able to increase [(3)H]MK-801 binding in a dose-dependent manner under these conditions were named Glyxins. Here we report that GLYX-13, a tetrapeptide (TPPT-amide), was found to readily cross the blood-brain barrier and modulate the NMDA receptor in a glycine-like fashion when examined pharmacologically and electrophysiologically. When GLYX-13 was administered to rats at 0.5-1.0mg/kg i.v., a significant enhancement in learning was observed using a hippocampus-dependent trace eye blink conditioning paradigm. These data indicate that the Glyxins are a new class of NMDA receptor modulators that may have therapeutic potential. Based on the broad agonist range in vitro and the potent cognitive-enhancing properties in a valid in vivo model of learning, GLYX-13 is a new drug candidate with potential for the treatment of cognitive disorders.

Animals↗
PubMed2005

Body mass index extremes in a British adolescent gynecology clinic.

STUDY OBJECTIVE: To identify the prevalence of patients with BMI extremes (BMI>88% or < 2%) in our Adolescent Gynecology clinic and audit their weight management. DESIGN: Retrospective case series. SETTING: The Adolescent Gynecology Clinic of a British District General Hospital PARTICIPANTS: All patients aged 12-17 years when first seen in the Adolescent Gynecology clinic from 1997 to 2003. INTERVENTIONS: Retrospective data collection on biometry and weight management interventions. MAIN OUTCOME MEASURES: The percentage of obese (BMI>98(th) percentile for age), overweight (BMI 88(th)-98(th) percentile) and underweight (BMI < 2(nd) percentile) based on published percentile BMI curves for the UK adolescent population, the proportion of patients with extreme BMI that were offered intervention, the types of intervention offered, the proportion of patients whose BMI improved after the intervention, and the number of patients with BMI>88% among smokers were compared to non-smokers. RESULTS: Of the 125 patients 24% were obese, an additional 17% overweight and 1% underweight. The expected figures in the general population are 2%, 10% and 2% respectively (P < 0.001; test of a single proportion). Weight management intervention was offered to 47% of patients with extreme BMI. The BMI improved in 36% of the patients who were offered and 14% of patients who were not offered intervention (P=0.066; chi(2)). There was no statistically significant difference between smokers and non-smokers in the proportion of patients with BMI>88% (P=0.93; chi(2)). CONCLUSION: There is significantly increased prevalence of obese and overweight women among adolescent gynecological patients. The need for management of the BMI of these patients has not been always been recognized and treatment is not particularly effective. The results indicate a need for defined strategies and additional resources for obesity management.

Adolescent↗
PubMed2005

The NMDA receptor complex: a long and winding road to therapeutics.

Advances in our basic understanding of inhibitory and excitatory amino acid neurotransmission have provided the foundation for directed drug discovery programs to modulate inhibitory GABAergic and excitatory N-methyl-D-aspartate (NMDA) receptor-mediated synapses. Gamma-Amino butyric acid (GABA(A)) and NMDA receptors are complex ion channels formed by multiple protein subunits that act as binding sites for transmitter amino acids and as allosteric regulatory binding sites to regulate ion channel activity. In the case of the NMDA receptor complex, one such allosteric site binds the obligatory glycine and/or d-serine co-agonist. Historical data from preclinical and clinical studies of GABAergic agents have clearly demonstrated that direct receptor modulators lack sufficient therapeutic indices to warrant clinical utility. However, pharmacological modulation of allosteric sites of the GABA multimeric receptor has resulted in the clinical development of safe and efficacious agents, exemplified by the benzodiazepines. Research has also revealed a similar outcome for the NMDA receptor, with allosteric modulators demonstrating improved safety profiles in the modulation of excitatory amino acid (EAA) transmission compared with direct NMDA receptor antagonists. First-generation EAA drugs were low affinity channel blockers of the NMDA multimeric receptor complex and included the anesthetic agent ketamine and the Alzheimer's drug memantine. As predicted by preclinical studies, direct NMDA receptor antagonists (eg, selfotel (Novartis AG) and high-affinity channel blockers (eg, dizocilpine) failed in the clinic as a result of narrow therapeutic indices. More recent efforts have focused on glycine/d-serine co-agonist function. These approaches include partial glycine agonists, in their agonist dose-range, for cognitive improvement and for treating schizophrenia. Such partial glycine agonists are also being advanced for the treatment of neuropathic pain in the antagonist dose range. An alternate approach to partial glycine agonists is to inhibit the uptake carrier(s) for glycine (ie, GlyT-1 and GlyT-2), thereby potentiating the lifetime of synaptic glycine. A number of glycine uptake inhibitors have been reported and their preclinical profiles support investigation into their utility in treating schizophrenia.

Clinical Trials, Phase III as Topic↗
PubMed2003

Multifunctional drugs for endothelial dysfunction in diabetes and glaucoma.

Endothelial dysfunction is a multifactorial term in that it encompasses a number of complex biochemical alterations in the ability of endothelial cells to perform their normal physiological function. These alterations are generally initiated by increased oxidative stress leading to pathological alterations in the cellular balance of mediators produced by endothelial cells. The key mediators include nitric oxide (NO), superoxide and endothelin. This review presents the current status of our knowledge of endothelial dysfunction in diabetes and in glaucoma and presents the case for evaluation of multifunctional drugs in these diseases.

Anti-Inflammatory Agents↗
PubMed2002

Nitrones, their value as therapeutics and probes to understand aging.

The nitrone-based free radical traps have significant potential in the treatment of neurodegenerative diseases as well as in the prolongation of life span. The mass action free radical trapping activity of these compounds is the property, which first brought them to the attention of the scientific community. Nevertheless extensive research has demonstrated that these reactions are not responsible for their therapeutic mechanistic basis of activity. Rather the mechanism of action in the case of their neuroprotective activity appears to involve the inhibition of enhanced signal transduction processes that mediate the upregulation of genes, which produce neurotoxic products. The most widely used compound in this series, alpha-phenyl-tert-butyl-nitrone (PBN), has been shown to extend life span in three published studies, i.e. two mouse models and one rat model. Significant prolongation of life span was noted in all three studies. We report the summary of a recent study with a novel nitrone, CPI-1429, which demonstrated the ability to extend life span even though administration of the compound was begun in older animals. Despite these promising studies, much more rigorous research examining the anti-aging activity of the nitrones needs to be conducted. It is not known exactly why the nitrones possess anti-aging activity. They have been shown to quell enhanced signal transduction processes associated with enhanced pro-inflammatory cytokine mediated events. The nitrones interfere in some unknown steps preventing receptor triggered MAP kinase phosphorylation cascades. Stabilization of phosphorylation networks associated with checkpoint proteins could slow cell cycle processes and this could be the basis of the nitrones anti-senescent activity.

Aging↗
PubMed2002

Nitrones as neuroprotectants and antiaging drugs.

Specific nitrones have been used for more than 30 years in analytical chemistry and biochemistry to trap and stabilize free radicals for the purpose of their identification and characterization. PBN (alpha-phenyl-tert-butyl nitrone), one of the more widely used nitrones for this purpose, has been shown to have potent pharmacologic activities in models of a number of aging-related diseases, most notably the neurodegenerative diseases of stroke and Alzheimer's disease. Studies in cell and animal models strongly suggest that PBN has potent antiaging activity. A novel nitrone, CPI-1429, has been shown to extend the life span of mice when administration was started in older animals. It has also shown efficacy in the prevention of memory dysfunction associated with normal aging in a mouse model. Mechanistic studies have shown that the neuroprotective activity of nitrones is not due to mass-action free radical-trapping activity, but due to cessation of enhanced signal transduction processes associated with neuroinflammatory processes known to be enhanced in several neurodegenerative conditions. Enhanced neuroinflammatory processes produce higher levels of neurotoxins, which cause death or dysfunction of neurons. Therefore, quelling of these processes is considered to have a beneficial effect allowing proper neuronal functioning. The possible antiaging activity of nitrones may reside in their ability to quell enhanced production of reactive oxygen species associated with age-related conditions. On the basis of novel ideas about the action of secretory products formed by senescent cells on bystander cells, it is postulated that nitrones will mitigate these processes and that this may be the mechanism of their antiaging activity.

Aging↗