James A Dykens

University of North Texas HSC at Fort Worth, Fort Worth, TX, United States

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Publications (27)84.81 Total impact

  • Yvonne Will, James A. Dykens
    12/2009; , ISBN: 9780470744307
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    ABSTRACT: Mitochondria have become a primary focus in our search not only for the mechanism(s) of neuronal death but also for neuroprotective drugs and therapies that can delay or prevent Alzheimer's disease and other chronic neurodegenerative conditions. This is because mitochrondria play a central role in regulating viability and death of neurons, and mitochondrial dysfunction has been shown to contribute to neuronal death seen in neurodegenerative diseases. In this article, we review the evidence for the role of mitochondria in cell death and neurodegeneration and provide evidence that estrogens have multiple effects on mitochondria that enhance or preserve mitochondrial function during pathologic circumstances such as excitotoxicity, oxidative stress, and others. As such, estrogens and novel non-hormonal analogs have come to figure prominently in our efforts to protect neurons against both acute brain injury and chronic neurodegeneration.
    Biochimica et Biophysica Acta 11/2009; 1800(10):1113-20. · 4.66 Impact Factor
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    ABSTRACT: 17-Estradiol is a less feminizing isomer of the potent hormonal estrogen, 17β-estradiol. 17-Estradiol is an orally active small molecule with conflicting reports of efficacy in preclinical models of degenerative diseases. A number of studies suggest neuroprotective potential in human neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease. Several studies have established an antioxidant effect of 17-estradiol in humans. The sodium salt of 17-estradiol 3-sulfate is a minor component (2.5–9.5%) of several widely marketed estrogen hormone replacement products, such as Premarin®, that are approved by the U.S. Food and Drug Administration and have been prescribed and studied in women and men for more than 65 years. Most of the more than 100 published reports on the neurological effects of feminizing estrogens found positive responses in at least one measure relating to cognition or prevention and treatment of AD, notwithstanding the negative results in the Women's Health Initiative studies. Whether these limited, and often not statistically significant, findings are clinically meaningful remains unknown. In many in vitro and in vivo preclinical neuroprotection and related studies, 17-estradiol and 17β-estradiol are active at similar concentrations and doses. However, 17-estradiol is less pleiotropic than 17β-estradiol, and thus its potential toxicity might be lower. Given decades of mixed reports regarding the potential efficacy and safety of strongly feminizing hormones in neurodegenerative diseases, the weakly feminizing 17-estradiol might be a suitable candidate for clinical testing of the neuroprotective potential of this chemical class because it avoids, or significantly reduces, the adverse effects of potent hormonal compounds. Drug Dev Res 70:1–21, 2009. © 2009 Wiley-Liss, Inc.
    Drug Development Research 02/2009; 70(1):1 - 21. · 0.87 Impact Factor
  • Walter H. Moos, James A. Dykens, Neil Howell
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    ABSTRACT: Alzheimer's disease (AD) is a major neurodegenerative disorder in the elderly and is the most common form of dementia. Approved AD drugs like donepezil and memantine provide some cognitive benefits to a subset of patients. However, the cost burden of AD will continue to increase in the absence of more effective drugs that treat its symptoms and ultimately slow its progression or delay or prevent its onset. A substantial number of studies report that 17β-estradiol (E2; estrogen), a potent endogenous feminizing hormone, is neuroprotective. Unfortunately, negative results from the Women's Health Initiative (WHI) and its ancillary Memory Study (WHIMS) have overshadowed the positive data collected over several decades. Importantly, there are a number of reasons why the WHIMS results should not be generalized to less- or non-feminizing estrogens. For the sake of argument, consider “non-hormonal” or non-feminizing estrogens to be worthwhile drug development candidates for AD and other neurodegenerative conditions because they have the potential to retain the positive neuroprotective activities of E2 while reducing the potential complications associated with feminizing hormones. Because the literature comparing estrogenicity of various estrogens is complex and spans multiple decades, we summarize herein the available hormonal comparisons of a common less-feminizing estrogen, 17-estradiol (17E2), with E2. 17E2 is less feminizing than E2 in every published study where reasonable comparisons can be made. One-half of these studies report a difference of two orders of magnitude or greater. In practice, compounds like 17E2 may prove to be largely non-feminizing at doses to be explored in human clinical trials. Moreover, other novel E2 analogues have been identified that are essentially devoid of feminizing actions. If the positive effects of feminizing estrogens on neurodegeneration prove useful in treating neurodegenerative diseases, less-feminizing and non-feminizing estrogen analogues may be even more effective, safer, and better tolerated. Drug Dev Res 69:177–184, 2008. © 2008 Wiley-Liss, Inc.
    Drug Development Research 08/2008; 69(4):177 - 184. · 0.87 Impact Factor
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    ABSTRACT: Cardiovascular disease has recently been suggested to be a significant complication of cancer treatment with several kinase inhibitors. In some cases, the mechanisms leading to cardiotoxicity are postulated to include mitochondrial dysfunction, either as a primary or secondary effect. Detecting direct effects on mitochondrial function, such as uncoupling of oxidative phosphorylation or inhibition of electron transport chain components, as well as identifying targets within the mitochondrial electron transport chain, can be accomplished in vitro. Here, we examined the effects of the tyrosine kinase inhibitor drugs imatinib, dasatinib, sunitinib, and sorafenib on ATP content in H9c2 cells grown under conditions where cells are either glycolytically or aerobically poised. Furthermore, we measured respiratory capacity of isolated rat heart mitochondria in the presence of the four kinase inhibitors and examined their effect on each of the oxidative phosphorylation complexes. Of the four kinase inhibitors examined, only sorafenib directly impaired mitochondrial function at clinically relevant concentrations, potentially contributing to the cytotoxic effect of the drug. For the other three kinase inhibitors lacking direct mitochondrial effects, altered kinase and other signaling pathways, are a more reasonable explanation for potential toxicity.
    Toxicological Sciences 08/2008; 106(1):153-61. · 4.33 Impact Factor
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    ABSTRACT: Mitochondrial toxicity is increasingly implicated in a host of drug-induced organ toxicities, including hepatotoxicity. Nefazodone was withdrawn from the U.S. market in 2004 due to hepatotoxicity. Accordingly, we evaluated nefazodone, another triazolopyridine trazodone, plus the azaspirodecanedione buspirone, for cytotoxicity and effects on mitochondrial function. In accord with its clinical disposition, nefazodone was the most toxic compound of the three, trazodone had relatively modest effects, whereas buspirone showed the least toxicity. Nefazodone profoundly inhibited mitochondrial respiration in isolated rat liver mitochondria and in intact HepG2 cells where this was accompanied by simultaneous acceleration of glycolysis. Using immunocaptured oxidative phosphorylation (OXPHOS) complexes, we identified Complex 1, and to a lesser amount Complex IV, as the targets of nefazodone toxicity. No inhibition was found for trazodone, and buspirone showed 3.4-fold less inhibition of OXPHOS Complex 1 than nefazodone. In human hepatocytes that express cytochrome P450, isoform 3A4, after 24 h exposure, nefazodone and trazodone collapsed mitochondrial membrane potential, and imposed oxidative stress, as detected via glutathione depletion, leading to cell death. Our results suggest that the mitochondrial impairment imposed by nefazodone is profound and likely contributes to its hepatotoxicity, especially in patients cotreated with other drugs with mitochondrial liabilities.
    Toxicological Sciences 07/2008; 103(2):335-45. · 4.33 Impact Factor
  • James W Simpkins, James A Dykens
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    ABSTRACT: Oxidative stress, bioenergetic failure and mitochondrial dysfunction are all implicated in the etiology of neurodegenerative diseases such as Alzheimer's disease (AD). The mitochondrial involvement in neurodegenerative diseases reflects the regulatory role mitochondrial failure plays in both necrotic cell death and apoptosis. The potent feminizing hormone, 17 beta-estradiol (E2), is neuroprotective in a host of cell and animal models of stroke and neurodegenerative diseases. The discovery that 17alpha-estradiol, an isomer of E2, is equally as neuroprotective as E2 yet is >200-fold less active as a hormone, has permitted development of novel, more potent analogs where neuroprotection is independent of hormonal potency. Studies of structure-activity relationships and mitochondrial function have led to a mechanistic model in which these steroidal phenols intercalate into cell membranes where they block lipid peroxidation reactions, and are in turn recycled. Indeed, the parental estrogens and novel analogs stabilize mitochondria under Ca(2+) loading otherwise sufficient to collapse membrane potential. The neuroprotective and mitoprotective potencies for a series of estrogen analogs are significantly correlated, suggesting that these compounds prevent cell death in large measure by maintaining functionally intact mitochondria. This therapeutic strategy is germane not only to sudden mitochondrial failure in acute circumstances, such as during a stroke or myocardial infarction, but also to gradual mitochondrial dysfunction associated with chronic degenerative disorders such as AD.
    Brain Research Reviews 03/2008; 57(2):421-30. · 7.82 Impact Factor
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    ABSTRACT: As a class, the biguanides induce lactic acidosis, a hallmark of mitochondrial impairment. To assess potential mitochondrial impairment, we evaluated the effects of metformin, buformin and phenformin on: 1) viability of HepG2 cells grown in galactose, 2) respiration by isolated mitochondria, 3) metabolic poise of HepG2 and primary human hepatocytes, 4) activities of immunocaptured respiratory complexes, and 5) mitochondrial membrane potential and redox status in primary human hepatocytes. Phenformin was the most cytotoxic of the three with buformin showing moderate toxicity, and metformin toxicity only at mM concentrations. Importantly, HepG2 cells grown in galactose are markedly more susceptible to biguanide toxicity compared to cells grown in glucose, indicating mitochondrial toxicity as a primary mode of action. The same rank order of potency was observed for isolated mitochondrial respiration where preincubation (40 min) exacerbated respiratory impairment, and was required to reveal inhibition by metformin, suggesting intramitochondrial bio-accumulation. Metabolic profiling of intact cells corroborated respiratory inhibition, but also revealed compensatory increases in lactate production from accelerated glycolysis. High (mM) concentrations of the drugs were needed to inhibit immunocaptured respiratory complexes, supporting the contention that bioaccumulation is involved. The same rank order was found when monitoring mitochondrial membrane potential, ROS production, and glutathione levels in primary human hepatocytes. In toto, these data indicate that biguanide-induced lactic acidosis can be attributed to acceleration of glycolysis in response to mitochondrial impairment. Indeed, the desired clinical outcome, viz., decreased blood glucose, could be due to increased glucose uptake and glycolytic flux in response to drug-induced mitochondrial dysfunction.
    Toxicology and Applied Pharmacology 01/2008; · 3.98 Impact Factor
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    ABSTRACT: Mitochondrial impairment is increasingly implicated in the etiology of toxicity caused by some thiazolidinediones, fibrates, and statins. We examined the effects of members of these drug classes on respiration of isolated rat liver mitochondria using a phosphorescent oxygen sensitive probe and on the activity of individual oxidative phosphorylation (OXPHOS) complexes using a recently developed immunocapture technique. Of the six thiazolidinediones examined, ciglitazone, troglitazone, and darglitazone potently disrupted mitochondrial respiration. In accord with these data, ciglitazone and troglitazone were also potent inhibitors of Complexes II+III, IV, and V, while darglitazone predominantly inhibited Complex IV. Of the six statins evaluated, lovastatin, simvastatin, and cerivastatin impaired mitochondrial respiration the most, with simvastatin and lovastatin impairing multiple OXPHOS Complexes. Within the class of fibrates, gemfibrozil more potently impaired respiration than fenofibrate, clofibrate, or ciprofibrate. Gemfibrozil only modestly inhibited Complex I, fenofibrate inhibited Complexes I, II+III, and V, and clofibrate inhibited Complex V. Our findings with the two complementary methods indicate that (1) some members of each class impair mitochondrial respiration, whereas others have little or no effect, and (2) the rank order of mitochondrial impairment accords with clinical adverse events observed with these drugs. Since the statins are frequently co-prescribed with the fibrates or thiazolidinediones, various combinations of these three drug classes were also analyzed for their mitochondrial effects. In several cases, the combination additively uncoupled or inhibited respiration, suggesting that some combinations are more likely to yield clinically relevant drug-induced mitochondrial side effects than others.
    Toxicology and Applied Pharmacology 10/2007; 223(3):277-87. · 3.98 Impact Factor
  • James A Dykens, Yvonne Will
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    ABSTRACT: Mitochondrial dysfunction is increasingly implicated in the etiology of drug-induced toxicities. Members of diverse drug classes undermine mitochondrial function, and among the most potent are drugs that have been withdrawn from the market, or have received Black Box warnings from the FDA. To avoid mitochondrial liabilities, routine screens need to be positioned within the drug-development process. Assays for mitochondrial function, cell models that better report mitochondrial impairment, and new animal models that more faithfully reflect clinical manifestations of mitochondrial dysfunction are discussed in the context of how such data can reduce late stage attrition of drug candidates and can yield safer drugs in the future.
    Drug Discovery Today 10/2007; 12(17-18):777-85. · 6.55 Impact Factor
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    ABSTRACT: Many highly proliferative cells generate almost all ATP via glycolysis despite abundant O(2) and a normal complement of fully functional mitochondria, a circumstance known as the Crabtree effect. Such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, such as the inhibitors rotenone, antimycin, oligomycin, and compounds like carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), that uncouple the respiratory electron transfer system from phosphorylation. These cells are also resistant to the toxicity of many drugs whose deleterious side effect profiles are either caused, or exacerbated, by impairment of mitochondrial function. Drug-induced mitochondrial toxicity is shown by members of important drug classes, including the thiazolidinediones, statins, fibrates, antivirals, antibiotics, and anticancer agents. To increase detection of drug-induced mitochondrial effects in a preclinical cell-based assay, HepG2 cells were forced to rely on mitochondrial oxidative phosphorylation rather than glycolysis by substituting galactose for glucose in the growth media. Oxygen consumption doubles in galactose-grown HepG2 cells and their susceptibility to canonical mitochondrial toxicants correspondingly increases. Similarly, toxicity of several drugs with known mitochondrial liabilities is more readily apparent in aerobically poised HepG2 cells compared to glucose-grown cells. Some drugs were equally toxic to both glucose- and galactose-grown cells, suggesting that mitochondrial impairment is likely secondary to other cytotoxic mechanisms.
    Toxicological Sciences 07/2007; 97(2):539-47. · 4.33 Impact Factor
  • James A Dykens, Lisa D Marroquin, Yvonne Will
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    ABSTRACT: Mitochondrial dysfunction is increasingly implicated in the etiology of drug-induced toxicities and negative side-effect profiles. Early identification of mitochondrial liabilities for new chemical entities is therefore crucial for avoiding late-stage attrition during drug development. Limitations of traditional methods for assessing mitochondrial dysfunction have discouraged routine evaluation of mitochondrial liabilities. To circumvent this bottleneck, a high-throughput screen has been developed that measures oxygen consumption; one of the most informative parameters for the assessment of mitochondrial status. This technique has revealed that some, but not all, members of many major drug classes have mitochondrial liabilities. This dichotomy encourages optimism that efficacy can be disassociated from mitochondrial toxicity, resulting in safer drugs in the future.
    Expert Review of Molecular Diagnostics 04/2007; 7(2):161-75. · 4.09 Impact Factor
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    ABSTRACT: Neuroprotective effects of estrogens have been shown in various in vitro and in vivo models, but the mechanisms underlying protection by estrogen are not clear. Mounting evidence suggests antioxidant effects contribute to the neuroprotective effects of estrogens. In the present study, we assessed the protective effects of estrogens against H2O2-induced toxicity in human neuroblastoma cells and the potential mechanisms involved in this protection. We demonstrate that 17beta-estradiol (17beta-E2) increases cell survival against H2O2 toxicity in human neuroblastoma cells. 17beta-E2 effectively reduced lipid peroxidation induced by 5-min H2O2 exposure. Furthermore, 17beta-E2 exerts the protective effects by maintaining intracellular Ca2+ homeostasis, attenuating ATP depletion, ablating mitochondrial calcium overloading, and preserving mitochondrial membrane potential. Two nonfeminizing estrogens, 17alpha- and ent-estradiol, were as effective as 17beta-E2 in increasing cell survival, alleviating lipid peroxidation, preserving mitochondrial function, and maintaining intracellular glutathione levels and Ca2+ homeostasis against H2O2 insult. Moreover, the estrogen receptor antagonist fulvestrant (ICI 182,780) did not block effects of 17beta-E2, but increased cell survival and blunted intracellular Ca2+ increases. However, these estrogens failed to reduce cytosolic reactive oxygen species, even at concentrations as high as 10 microM. In conclusion, estrogens exert protective effects against oxidative stress by inhibiting lipid peroxidation and subsequently preserving Ca2+ homeostasis, mitochondrial membrane potential, and ATP levels.
    Molecular Pharmacology 08/2006; 70(1):395-404. · 4.41 Impact Factor
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    Meharvan Singh, James A Dykens, James W Simpkins
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    ABSTRACT: Estrogens are gonadal steroid hormones that are present in the circulation of both males and females and that can no longer be considered within the strict confines of reproductive function. In fact, the bone, the cardiovascular system, and extrahypothalamic regions of the brain are now well-established targets of estrogens. Among the numerous aspects of brain function regulated by estrogens are their effects on mood, cognitive function, and neuronal viability. Here, we review the supporting evidence for estrogens as neuroprotective agents and summarize the various mechanisms that may be involved in this effect, focusing particularly on the mitochondria as an important target. On the basis of this evidence, we discuss the clinical applicability of estrogens in treating various age-related disorders, including Alzheimer disease and stroke, and identify the caveats that must be considered.
    Experimental Biology and Medicine 06/2006; 231(5):514-21. · 2.80 Impact Factor
  • Neil Howell, James Dykens, Walter H. Moos
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    ABSTRACT: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, affecting more than 4 million Americans, and it is a huge drain on health care resources. Moreover, the cost burden of AD will increase substantially without the development of drugs that prevent its onset or slow its progression. At the present time, the available AD drugs provide, at best, temporary cognitive improvement, and cost-benefit analyses indicate no more than marginal support for their use. AD is a disorder of complex etiology that is characterized by the formation of amyloid plaques and neurofibrillary tangles in the brain. The Amyloid Cascade model of AD neurodegeneration postulates that the primary disease process is the deposition of amyloid plaques and their subsequent effects on cognition. However, as we review here, the emerging evidence argues against simple linear models of neurodegeneration in AD patients, and more complex models of etiology and pathogenesis are needed as part of the drug development process. As one potential therapeutic approach, there is substantial evidence that estrogens are neuroprotective and act on a number of neural pathways, many of which are compromised in AD. A number of studies have shown that estrogens provide clinical benefit in AD patients and in other neurodegenerative disorders. Unfortunately, the negative results of the Women's Health Initiative Memory Study (WHIMS) have overshadowed the positive results from the last four decades. However, as discussed here, there are a number of reasons why the WHIMS results should not be generalized. On balance, estrogens remain a fruitful drug development approach for AD, and other neurodegenerative conditions, and especially those estrogen compounds or analogues that avoid or minimize the complications associated with long-term use of feminizing hormones in post-menopausal women. Drug Dev. Res. 66:53–77, 2006. © 2006 Wiley-Liss, Inc.
    Drug Development Research 02/2006; 66(2):53 - 77. · 0.87 Impact Factor
  • James A. Dykens, Christophe Wersinger, Anita Sidhu
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    ABSTRACT: Despite compelling literature documenting the cyto- and neuro-protective activities of various estrogens in a wide variety of cell and animal models, several large clinical trials of hormone replacement therapies have failed to detect such beneficial responses in humans. To some degree, this failure stems from profound hormonal responses that counterbalance the protective effects. This limitation could be circumvented by the development of less hormonally active estrogen analogs that retain the cytoprotective activities of the parental hormones. For example, 17α-estradiol (17α-E2) is at least 200-fold less active than 17β-estradiol (17β-E2) as a transactivating hormone, yet it is equipotent as a cytoprotectant in many cell types exposed to a variety of stressors, such as amyloid toxicity, serum withdrawal, oxidative stress, and glutamate excitotoxicity. Both estradiol isomers stabilize mitochondrial function under pathogenic conditions, and both have shown efficacy in animal models of stroke. The results for models of Parkinson's disease differ, and 17β-E2, but not 17α-E2, has been reported previously to provide neuroprotection against MPTP toxicity. However, such findings must be regarded in light of reports that 17β-E2 impedes cellular uptake of MPTP by the dopamine transporter (DAT), thereby forestalling development of the lesion rather than providing authentic cytoprotection. We report here that both 17α-E2 and 17β-E2 show classical, non-competitive, inhibition of dopamine uptake by the human DAT (hDAT) transfected into Ltk− mouse fibroblasts, HEK293 human embryonic kidney cells, and SH-SY5Y human neuroblastoma cells. IC50 values vary slightly with cell type, but are 400 and 70 nM for 17α-E2 and 17β-E2, respectively, in SH-SY5Y cells. We also evaluated 17α-E2 in the 6-OH-dopamine (6-OHDA) model of PD, where toxin uptake occurs via the DAT. In these studies, treatment with estrogen was delayed for 6 hr after unilateral intrastriatal 6-OHDA injection to allow for toxin uptake. After 6 hr, a loading dose of 17α-E2 (100 µg/kg in sesame oil) was injected s.c., accompanied by implanting of a sustained release silastic device. After 21 days, animals treated with 17α-E2 showed significant improvements in both gait asymmetry and apo-morphine induced rotational defects. These positive results encourage evaluation of 17α-E2 in a host of neurodegenerative diseases. Drug Dev. Res. 66:160–171, 2006. © 2006 Wiley-Liss, Inc.
    Drug Development Research 02/2006; 66(2):160 - 171. · 0.87 Impact Factor
  • James A Dykens, Walter H Moos, Neil Howell
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    ABSTRACT: 17alpha-estradiol (17alpha-E2) differs from its isomer, the potent feminizing hormone 17beta-estradiol (17beta-E2), only in the stereochemistry at one carbon, but this is sufficient to render it at least 200-fold less active as a transactivating hormone. Despite its meager hormonal activity, 17alpha-E2 is as potent as 17beta-E2 in protecting a wide variety of cell types, including primary neurons, from a diverse array of lethal and etiologically relevant stressors, including amyloid toxicity, serum withdrawal, oxidative stress, excitotoxicity, and mitochondrial inhibition, among others. Moreover, both estradiol isomers have shown efficacy in animal models of stroke, Alzheimer's disease (AD), and Parkinson's disease (PD). Data from many labs have yielded a mechanistic model in which 17alpha-E2 intercalates into cell membranes, where it terminates lipid peroxidation chain reactions, thereby preserving membrane integrity, and where it in turn is redox cycled by glutathione or by NADPH through enzymatic coupling. Maintaining membrane integrity is critical to mitochondrial function, where loss of impermeability of the inner membrane initiates both necrotic and apoptotic pathways. Thus, by serving as a mitoprotectant, 17alpha-E2 forestalls cell death and could correspondingly provide therapeutic benefit in a host of degenerative diseases, including AD, PD, Friedreich's ataxia, and amyotrophic lateral sclerosis, while at the same time circumventing the common adverse effects elicited by more hormonally active analogues. Positive safety and pharmacokinetic data from a successful phase I clinical study with oral 17alpha-E2 (sodium sulfate conjugate) are presented here, and several options for its future clinical assessment are discussed.
    Annals of the New York Academy of Sciences 07/2005; 1052:116-35. · 4.38 Impact Factor
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    ABSTRACT: Oxidative stress, bioenergetic impairment and mitochondrial failure have all been implicated in the etiology of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), as well as retinal degeneration in glaucoma and retinitis pigmentosa. Moreover, at least 75 debilitating, and often lethal, diseases are directly attributable to deletions or mutations in mitochondrial DNA, or in nuclear-encoded proteins destined for delivery to the mitochondria. Such widespread mitochondrial involvement in disease reflects the regulatory position mitochondrial failure plays in both acute necrotic cell death, and in the less catastrophic process of apoptosis. The potent feminizing hormone, 17 beta-estradiol (E2), has shown cytoprotective activities in a host of cell and animal models of stroke, myocardial infarct and neurodegenerative diseases. The discovery that 17alpha-estradiol, an isomer of E2, is equally as cytoprotective as E2 yet is >200-fold less active as a hormone, has permitted development of novel, more potent analogs where cytoprotection is independent of hormonal potency. Studies of structure-activity-relationships, glutathione interactions and mitochondrial function have led to a mechanistic model in which these steroidal phenols intercalate into cell membranes where they block lipid peroxidation reactions, and are in turn recycled via glutathione. Such a mechanism would be particularly germane in mitochondria where function is directly dependent on the impermeability of the inner membrane, and where glutathione levels are maintained at extraordinarily high 8-10mM concentrations. Indeed, the parental estrogens and novel analogs stabilize mitochondria under Ca(2+) loading otherwise sufficient to collapse membrane potential. The cytoprotective and mitoprotective potencies for 14 of these analogs are significantly correlated, suggesting that these compounds prevent cell death in large measure by maintaining functionally intact mitochondria. This therapeutic strategy is germane not only to sudden mitochondrial failure in acute circumstances, such as during a stroke or myocardial infarction, but also to gradual mitochondrial dysfunction associated with chronic degenerative disorders such as AD, PD and HD.
    Current Drug Targets - CNS & Neurological Disorders 03/2005; 4(1):69-83.
  • Neil Howell, James Dykens, Walter H. Moos
    Drug Development Research - DRUG DEVELOP RES. 01/2005; 66(2):51-52.
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    ABSTRACT: The cytoprotective activity of MITO-4565, a novel, non-hormonal, estradiol derivative, was evaluated in the S334ter transgenic model of retinitis pigmentosa (RP). Progressive blindness in RP is due to apoptotic death of the photoreceptors, a process mimicked by the animal models [Portera-Cailliau C, Sung C-H, Nathans J, Adler R. Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. Proc Natl Acad Sci USA 1994;91:974-8]. On postnatal day 9, 10 transgenic S334ter rats received a single intraocular injection of MITO-4565 in the left eye, and vehicle in the right eye. By postnatal day 20, the thickness of the outer nuclear layer (ONL) in the superior retina of the untreated eyes was 5.76 +/- 1.12 microm (N = 10), versus 10.72 +/- 1.52 microm (N = 10) for eyes treated with MITO-4565 (P < 0.0001, ANOVA F = 1671). Comparable cytoprotection was also observed for the inferior retina. Cytoprotection by MITO-4565 was also observed in primary cultures of rat retinal ganglion cells against NMDA excitotoxicity. Data from studies of hexose monophosphate shunt flux, mitochondrial stability, and in vitro lipid peroxidation, are in accord with previous reports [Green PS, Gridley KE, Simpkins JW. Nuclear estrogen receptor independent neuroprotection by estratrienes: a novel interaction with glutathione. Neuroscience 1997;84:7-10]; a likely mechanism of action entails moderation of membrane lipid peroxidation in a redox couple with glutathione. Such preservation of membrane integrity is particularly crucial to mitochondria, where collapse of membrane potential precipitates cell death, and where GSH is maintained at mM concentrations. Indeed, exposure to MITO-4565, but not a methoxy substituted negative control, allowed mitochondria to retain membrane potential (DeltaPsi(m)) under conditions of Ca(2+) overload that would normally induce complete mitochondrial failure. Mitochondrial interventions offer a novel therapeutic approach for RP, and other degenerative diseases of the retina.
    Biochemical Pharmacology 12/2004; 68(10):1971-84. · 4.58 Impact Factor

Publication Stats

1k Citations
84.81 Total Impact Points


  • 2004–2009
    • University of North Texas HSC at Fort Worth
      • Department of Pharmacology and Neuroscience
      Fort Worth, TX, United States
  • 2006–2008
    • Texas Tech University Health Sciences Center
      • Department of Pharmacology and Neuroscience
      Lubbock, TX, United States
    • California College San Diego
      San Diego, California, United States
    • University of Texas Medical Branch at Galveston
      Galveston, Texas, United States
  • 2007
    • Wyeth
      New Johnsonville, Tennessee, United States
    • Pfizer Inc.
      New York City, New York, United States