Publications - Salk Institute for Biological Studies

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Dafre, A.L., Zahid, S., Probst, J.J., Currais, A., Yu, J., Schubert, D., Maher, P. CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction. (2024) Aging. 16. DOI: 10.18632/aging.205673

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Liang, Z., Candib, A., Soriano-Castell, D., Fischer, W., Finley, K., Maher, P. Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders. (2024) Redox Biol. 72:103138. DOI: 10.1016/j.redox.2024.103138

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Tolan, A.J., Sanchez, K.L., Shin, S.D., White, J.B., Currais, A., Soriano-Castell, D., Wilson, C.G., Maher, P., Soriano, S. Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann-Pick Disease Type C. (2024) Genes (Basel). 15(1). DOI: 10.3390/genes15010101

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Dos Santos, B., Bion, M.C., Goujon-Svrzic, M., Maher, P., Dafre, A.L. REAP+: A single preparation for rapid isolation of nuclei, cytoplasm, and mitochondria. (2023) Analytical Biochemistry.:115445 DOI: 10.1016/j.ab.2023.115445

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Ates, G., Taguchi, T., Maher, P. CMS121 Partially Attenuates Disease Progression in Mouse Models of Huntington's Disease. (2023) Molecular Neurobiology. DOI: 10.1007/s12035-023-03711-2

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Zahid, S., Dafre, A.L., Currais, A., Yu, J., Schubert, D., Maher, P. The Geroprotective Drug Candidate CMS121 Alleviates Diabetes, Liver Inflammation, and Renal Damage in db/db Leptin Receptor Deficient Mice. (2023) Int J Mol Sci. 24(7). DOI: 10.3390/ijms24076828

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Pham, T.B., Boussaty, E.C., Currais, A., Maher, P., Schubert, D.R., Manor, U., Friedman, R.A. Attenuation of Age-Related Hearing Impairment in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice Treated with Fatty Acid Synthase Inhibitor CMS121. (2023) Journal of Molecular Neuroscience. DOI: 10.1007/s12031-023-02119-w

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Liang, Z., Maher, P. Structural Requirements for the Neuroprotective and Anti-Inflammatory Activities of the Flavanone Sterubin. (2022) Antioxidants (Basel). 11(11). DOI: 10.3390/antiox11112197

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Cabral, C., Carbone, C., Maher, P., Castelo-Branco, M. Editorial: Psychoactive natural products: Potential in the treatment of brain diseases and strategies to improve delivery. (2022) Front Pharmacol. 13:1032496. DOI: 10.3389/fphar.2022.1032496

Tan, D., Konduri, S., Erikci Ertunc, M., Zhang, P., Wang, J., Chang, T., Pinto, A.F.M., Rocha, A., Donaldson, C.J., Vaughan, J.M., Ludwig, R.G., Willey, E., Iyer, M., Gray, P.C., Maher, P., Allen, N.J., Zuchero, J.B., Dillin, A., Mori, M.A., Kohama, S.G., Siegel, D., Saghatelian, A. A class of anti-inflammatory lipids decrease with aging in the central nervous system. (2022) Nature Chemical Biology. DOI: 10.1038/s41589-022-01165-6

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Currais, A., Kepchia, D., Liang, Z., Maher, P. The Role of AMP-activated Protein Kinase (AMPK) in Oxytosis/Ferroptosis: Protector or Potentiator? (2022) Antioxid Redox Signal. DOI: 10.1089/ars.2022.0013

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Liang, Z., Soriano-Castell, D., Kepchia, D., Duggan, B.M., Currais, A., Schubert, D., Maher, P. Cannabinol inhibits oxytosis/ferroptosis by directly targeting mitochondria independently of cannabinoid receptors. (2022) Free Radical Biology & Medicine. DOI: 10.1016/j.freeradbiomed.2022.01.001

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Kepchia, D., Huang, L., Currais, A., Liang, Z., Fischer, W., Maher, P. The Alzheimer's disease drug candidate J147 decreases blood plasma fatty acid levels via modulation of AMPK/ACC1 signaling in the liver. (2022) Biomed Pharmacother. 147:112648. DOI: 10.1016/j.biopha.2022.112648

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Soriano-Castell, D., Liang, Z., Maher, P., Currais, A. Profiling the chemical nature of anti-oxytotic/ferroptotic compounds with phenotypic screening. (2021) Free Radical Biology & Medicine.:313-325 DOI: 10.1016/j.freeradbiomed.2021.11.003

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Because old age is the greatest risk factor for Alzheimer's disease (AD), it is critical to target the pathological events that link aging to AD in order to develop an efficient treatment that acts upon the primary causes of the disease. One such event might be the activation of oxytosis/ferroptosis, a unique cell death mechanism characterized by mitochondrial dysfunction and lethal lipid peroxidation. Here, a comprehensive library of >900 natural compounds was screened for protection against oxytosis/ferroptosis in nerve cells with the goal of better understanding the chemical nature of inhibitors of oxytosis/ferroptosis. Although the compounds tested spanned structurally diverse chemical classes from animal, microbial, plant and synthetic origins, a small set of very potent anti-oxytotic/ferroptotic compounds was identified that was highly enriched in plant quinones. The ability of these compounds to protect against oxytosis/ferroptosis strongly correlated with their ability to protect against in vitro ischemia and intracellular amyloid-beta toxicity in nerve cells, indicating that aspects of oxytosis/ferroptosis also underly other toxicities that are relevant to AD. Importantly, the anti-oxytotic/ferroptotic character of the quinone compounds relied on their capacity to target and directly prevent lipid peroxidation in a manner that required the reducing activity of cellular redox enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1) and ferroptosis suppressor protein 1 (FSP1). Because some of the compounds increased the production of total reactive oxygen species while decreasing lipid peroxidation, it appears that the pro-oxidant character of a compound can coexist with an inhibitory effect on lipid peroxidation and, consequently, still prevent oxytosis/ferroptosis. These findings have significant implications for the understanding of oxytosis/ferroptosis and open new approaches to the development of future neurotherapies.

Soriano-Castell, D., Currais, A., Maher, P. Defining a Pharmacological Inhibitor Fingerprint for Oxytosis/Ferroptosis. (2021) Free Radical Biology & Medicine. DOI: 10.1016/j.freeradbiomed.2021.05.023

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Soriano-Castell, D., Liang, Z., Maher, P., Currais, A. The search for anti-oxytotic/ferroptotic compounds in the plant world. (2021) Br J Pharmacol. DOI: 10.1111/bph.15517

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Kepchia, D., Currais, A., Dargusch, R., Finley, K., Schubert, D., Maher, P. Geroprotective effects of Alzheimer's disease drug candidates. (2021) Aging. 13. DOI: 10.18632/aging.202631

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Maher, P. Preventing and Treating Neurological Disorders with the Flavonol Fisetin. (2021) Brain Plast. 6(2):155-166. DOI: 10.3233/BPL-200104

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Maher, P. Investigations into the Role of Metabolism in the Inflammatory Response of BV2 Microglial Cells. (2021) Antioxidants (Basel). 10(1). DOI: 10.3390/antiox10010109

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Maher, P., Currais, A., Schubert, D. Using the Oxytosis/Ferroptosis Pathway to Understand and Treat Age-Associated Neurodegenerative Diseases. (2020) Cell Chemical Biology. DOI: 10.1016/j.chembiol.2020.10.010

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Maher, P. Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. (2020) Antioxidants (Basel). 9(11). DOI: 10.3390/antiox9111113

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Liang, Z., Currais, A., Soriano-Castell, D., Schubert, D., Maher, P. Natural products targeting mitochondria: emerging therapeutics for age-associated neurological disorders. (2020) Pharmacol Ther.:107749 DOI: 10.1016/j.pharmthera.2020.107749

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Huang, L., McClatchy, D.B., Maher, P., Liang, Z., Diedrich, J.K., Soriano-Castell, D., Goldberg, J., Shokhirev, M., Yates, J.R., Schubert, D., Currais, A. Intracellular amyloid toxicity induces oxytosis/ferroptosis regulated cell death. (2020) Cell Death & Disease. 11(10):828. DOI: 10.1038/s41419-020-03020-9

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Gunesch, S., Soriano-Castell, D., Lamer, S., Schlosser, A., Maher, P., Decker, M. Development and Application of a Chemical Probe Based on a Neuroprotective Flavonoid Hybrid for Target Identification Using Activity-Based Protein Profiling. (2020) ACS Chem Neurosci. DOI: 10.1021/acschemneuro.0c00589

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Ates, G., Goldberg, J., Currais, A., Maher, P. CMS121, a fatty acid synthase inhibitor, protects against excess lipid peroxidation and inflammation and alleviates cognitive loss in a transgenic mouse model of Alzheimer's disease. (2020) Redox Biology. 36:101648. DOI: 10.1016/j.redox.2020.101648

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Goldberg, J., Currais, A., Ates, G., Huang, L., Shokhirev, M., Maher, P., Schubert, D. Targeting of intracellular Ca stores as a therapeutic strategy against age-related neurotoxicities. (2020) NPJ Aging and Mechanisms of Disease. 6:10. DOI: 10.1038/s41514-020-00048-1

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Aguirre, C.A., Concetta Morale, M., Peng, Q., Sanchez-Alavez, M., Cintrón-Colón, R., Feng, K., Fazelpour, S., Maher, P., Conti, B. Two single nucleotide polymorphisms in IL13 and IL13RA1 from individuals with idiopathic Parkinson's disease increase cellular susceptibility to oxidative stress. (2020) Brain, Behavior, and Immunity. 88:920-924. DOI: 10.1016/j.bbi.2020.04.007

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Maher, P.A. Using Plants as a Source of Potential Therapeutics for the Treatment of Alzheimer's Disease. (2020) Yale J Biol Med. 93(2):365-373.

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Hofmann, J., Fayez, S., Scheiner, M., Hoffmann, M., Oerter, S., Appelt-Menzel, A., Maher, P., Maurice, T., Bringmann, G., Decker, M. Sterubin: Enantioresolution and Configurational Stability, Enantiomeric Purity in Nature, and Neuroprotective Activity in Vitro and in Vivo. (2020) Chemistry. 26(32):7299-7308. DOI: 10.1002/chem.202001264

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Maher, P., Fischer, W., Liang, Z., Soriano-Castell, D., Pinto, A.F.M., Rebman, J., Currais, A. The Value of Herbarium Collections to the Discovery of Novel Treatments for Alzheimer's Disease, a Case Made With the Genus . (2020) Front Pharmacol. 11:208. DOI: 10.3389/fphar.2020.00208

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Gunesch, S., Hoffmann, M., Kiermeier, C., Fischer, W., Pinto, A.F.M., Maurice, T., Maher, P., Decker, M. 7-O-Esters of taxifolin with pronounced and overadditive effects in neuroprotection, anti-neuroinflammation, and amelioration of short-term memory impairment in vivo. (2020) Redox Biol. 29:101378. DOI: 10.1016/j.redox.2019.101378

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Alzheimer's disease (AD) is a multifactorial disease and the most common form of dementia. There are no treatments to cure, prevent or slow down the progression of the disease. Natural products hold considerable interest for the development of preventive neuroprotectants to treat neurodegenerative disorders like AD, due to their low toxicity and general beneficial effects on human health with their anti-inflammatory and antioxidant features. In this work we describe regioselective synthesis of 7-O-ester hybrids of the flavonoid taxifolin with the phenolic acids cinnamic and ferulic acid, namely 7-O-cinnamoyltaxifolin and 7-O-feruloyltaxifolin. The compounds show pronounced overadditive neuroprotective effects against oxytosis, ferroptosis and ATP depletion in the murine hippocampal neuron HT22 cell model. Furthermore, 7-O-cinnamoyltaxifolin and 7-O-feruloyltaxifolin reduced LPS-induced neuroinflammation in BV-2 microglia cells as assessed by effects on the levels of NO, IL6 and TNFα. In all in vitro assays the 7-O-esters of taxifolin and ferulic or cinnamic acid showed strong overadditive activity, significantly exceeding the effects of the individual components and the equimolar mixtures thereof, which were almost inactive in all of the assays at the tested concentrations. In vivo studies confirmed this overadditive effect. Treatment of an AD mouse model based on the injection of oligomerized Aβ peptide into the brain to cause neurotoxicity and subsequently memory deficits with 7-O-cinnamoyltaxifolin or 7-O-feruloyltaxifolin resulted in improved performance in an assay for short-term memory as compared to vehicle and mice treated with the respective equimolar mixtures. These results highlight the benefits of natural product hybrids as a novel compound class with potential use for drug discovery in neurodegenerative diseases due to their pharmacological profile that is distinct from the individual natural components.

Dafre, A.L., Schmitz, A.E., Maher, P. Rapid and persistent loss of TXNIP in HT22 neuronal cells under carbonyl and hyperosmotic stress. (2019) Neurochemistry International.:104585 DOI: 10.1016/j.neuint.2019.104585

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Leclercq, K., Liefferinge, J.V., Albertini, G., Neveux, M., Dardenne, S., Mairet-Coello, G., Vandenplas, C., Deprez, T., Chong, S.A., Foerch, P., Bentea, E., Sato, H., Maher, P., Massie, A., Smolders, I., Kaminski, R.M. Anticonvulsant and antiepileptogenic effects of system inactivation in chronic epilepsy models. (2019) Epilepsia. 60(7):1412-1423. DOI: 10.1111/epi.16055

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Maher, P. The Potential of Flavonoids for the Treatment of Neurodegenerative Diseases. (2019) International Journal of Molecular Sciences. 20(12). DOI: 10.3390/ijms20123056

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Schubert, D., Kepchia, D., Liang, Z., Dargusch, R., Goldberg, J., Maher, P. Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer's Disease. (2019) Molecular Neurobiology. 56(11):7719-7730. DOI: 10.1007/s12035-019-1637-8

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Finding a therapy for Alzheimer's disease (AD) is perhaps the greatest challenge for modern medicine. The chemical scaffolds of many drugs in the clinic today are based upon natural products from plants, yet Cannabis has not been extensively examined as a source of potential AD drug candidates. Here, we determine if a number of non-psychoactive cannabinoids are neuroprotective in a novel pre-clinical AD and neurodegeneration drug-screening platform that is based upon toxicities associated with the aging brain. This drug discovery paradigm has yielded several compounds in or approaching clinical trials for AD. Eleven cannabinoids were assayed for neuroprotection in assays that recapitulate proteotoxicity, loss of trophic support, oxidative stress, energy loss, and inflammation. These compounds were also assayed for their ability to remove intraneuronal amyloid and subjected to a structure-activity relationship analysis. Pairwise combinations were assayed for their ability to synergize to produce neuroprotective effects that were greater than additive. Nine of the 11 cannabinoids have the ability to protect cells in four distinct phenotypic neurodegeneration screening assays, including those using neurons that lack CB1 and CB2 receptors. They are able to remove intraneuronal Aβ, reduce oxidative damage, and protect from the loss of energy or trophic support. Structure-activity relationship (SAR) data show that functional antioxidant groups such as aromatic hydroxyls are necessary but not sufficient for neuroprotection. Therefore, there is a need to focus upon CB1 agonists that have these functionalities if neuroprotection is the goal. Pairwise combinations of THC and CBN lead to a synergistic neuroprotective interaction. Together, these results significantly extend the published data by showing that non-psychoactive cannabinoids are potential lead drug candidates for AD and other neurodegenerative diseases.

Dafre, A.L., Schmitz, A.E., Maher, P. Hyperosmotic Stress Initiates AMPK-Independent Autophagy and AMPK- and Autophagy-Independent Depletion of Thioredoxin 1 and Glyoxalase 2 in HT22 Nerve Cells. (2019) Oxid Med Cell Longev. 2019:2715810. DOI: 10.1155/2019/2715810

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Fischer, W., Currais, A., Liang, Z., Pinto, A., Maher, P. Old age-associated phenotypic screening for Alzheimer's disease drug candidates identifies sterubin as a potent neuroprotective compound from Yerba santa. (2019) Redox Biol. 21:101089. DOI: 10.1016/j.redox.2018.101089

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Schubert, D., Currais, A., Goldberg, J., Finley, K., Petrascheck, M., Maher, P. Geroneuroprotectors: Effective Geroprotectors for the Brain. (2018) Trends in Pharmacological Sciences. 39(12):1004-1007. DOI: 10.1016/j.tips.2018.09.008

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Lewerenz, J., Ates, G., Methner, A., Conrad, M., Maher, P. Oxytosis/Ferroptosis-(Re-) Emerging Roles for Oxidative Stress-Dependent Non-apoptotic Cell Death in Diseases of the Central Nervous System. (2018) Frontiers in Neuroscience. 12:214. DOI: 10.3389/fnins.2018.00214

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Maher, P., Conti, B. Deciphering the pathways that protect from IL-13-mediated potentiation of oxidative stress-induced dopaminergic nerve cell death. (2018) Cytokine. 103:114-120. DOI: 10.1016/j.cyto.2017.09.018

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Schramm, S., Huang, G., Gunesch, S., Lang, F., Roa, J., Högger, P., Sabaté, R., Maher, P., Decker, M. Regioselective synthesis of 7-O-esters of the flavonolignan silibinin and SARs lead to compounds with overadditive neuroprotective effects. (2018) Eur J Med Chem. 146:93-107. DOI: 10.1016/j.ejmech.2018.01.036

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Maher, P. Potentiation of glutathione loss and nerve cell death by the transition metals iron and copper: Implications for age-related neurodegenerative diseases. (2018) Free Radical Biology & Medicine. 115:92-104. DOI: 10.1016/j.freeradbiomed.2017.11.015

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Goldberg, J., Currais, A., Prior, M., Fischer, W., Chiruta, C., Ratliff, E., Daugherty, D., Dargusch, R., Finley, K., Esparza-Moltó, P.B., Cuezva, J.M., Maher, P., Petrascheck, M., Schubert, D. The mitochondrial ATP synthase is a shared drug target for aging and dementia. (2018) Aging Cell. 17(2). DOI: 10.1111/acel.12715

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Maher, P. Protective effects of fisetin and other berry flavonoids in Parkinson's disease. (2017) Food & Function. 8(9):3033-3042. DOI: 10.1039/c7fo00809k

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Daugherty, D., Goldberg, J., Fischer, W., Dargusch, R., Maher, P., Schubert, D. A novel Alzheimer's disease drug candidate targeting inflammation and fatty acid metabolism. (2017) Alzheimers Res Ther. 9(1):50. DOI: 10.1186/s13195-017-0277-3

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Dafre, A.L., Schmitz, A.E., Maher, P. Methylglyoxal-induced AMPK activation leads to autophagic degradation of thioredoxin 1 and glyoxalase 2 in HT22 nerve cells. (2017) Free Radical Biology & Medicine. 108:270-279. DOI: 10.1016/j.freeradbiomed.2017.03.028

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Methylglyoxal (MGO) is a major glycating agent that reacts with basic residues of proteins and promotes the formation of advanced glycation end products which are believed to play key roles in a number of pathologies, such as diabetes, Alzheimer's disease, and inflammation. We previously showed that MGO treatment targets the thioredoxin and the glyoxalase systems, leading to a decrease in Trx1 and Glo2 proteins in immortalized mouse hippocampal HT22 nerve cells. Here, we propose that autophagy is the underlying mechanism leading to Glo2 and Trx1 loss induced by MGO. The autophagic markers p62, and the lipidated and active form of LC3, were increased by MGO (0.5mM). Autophagy inhibition with bafilomycin or chloroquine prevented the decrease in Trx1 and Glo2 at 6 and 18h after MGO treatment. Proteasome inhibition by MG132 exacerbated the effect of MGO on Trx1 and Glo2 degradation (18h), further suggesting a role for autophagy. ATG5 small interfering RNA protected Trx1 and Glo2 from MGO-induced degradation, confirming Trx1 and Glo2 loss is mediated by autophagy. In the search for the signals that control autophagy, we found that AMPK activation, a known autophagy inducer, was markedly increased by MGO treatment. AMPK activation was confirmed by increased acetyl coenzyme A carboxylase phosphorylation, a direct AMPK substrate and by decreased mTOR phosphorylation, an indirect marker of AMPK activation. To confirm that MGO-mediated Trx1 and Glo2 degradation was AMPK-dependent, AMPK-deficient mouse embryonic fibroblasts (MEFs) were treated with MGO. Wildtype MEFs presented the expected decrease in Trx1 and Glo2, while MGO was ineffective in decreasing these proteins in AMPK-deficient cells. Overall, the data indicate that MGO activates autophagy in an AMPK-dependent manner, and that autophagy was responsible for Trx1 and Glo2 degradation, confirming that Trx1 and Glo2 are molecular targets of MGO.

Currais, A., Farrokhi, C., Dargusch, R., Armando, A., Quehenberger, O., Schubert, D., Maher, P. Fisetin Reduces the Impact of Aging on Behavior and Physiology in the Rapidly Aging SAMP8 Mouse. (2017) J. Gerontol. A Biol. Sci. Med. Sci. 73(3):299-307. DOI: 10.1093/gerona/glx104

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Maher, P., van Leyen, K., Dey, P.N., Honrath, B., Dolga, A., Methner, A. The role of Ca(2+) in cell death caused by oxidative glutamate toxicity and ferroptosis. (2017) Cell Calcium. 70:47-55. DOI: 10.1016/j.ceca.2017.05.007

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Schmitz, A.E., de Souza, L.F., Dos Santos, B., Maher, P., Lopes, F.M., Londero, G.F., Klamt, F., Dafre, A.L. Methylglyoxal-Induced Protection Response and Toxicity: Role of Glutathione Reductase and Thioredoxin Systems. (2017) Neurotoxicity Research. 32(3):340-350. DOI: 10.1007/s12640-017-9738-5

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Mori, S., Sugama, S., Nguyen, W., Michel, T., Sanna, M.G., Sanchez-Alavez, M., Cintron-Colon, R., Moroncini, G., Kakinuma, Y., Maher, P., Conti, B. Lack of interleukin-13 receptor α1 delays the loss of dopaminergic neurons during chronic stress. (2017) Journal of Neuroinflammation. 14(1):88. DOI: 10.1186/s12974-017-0862-1

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Merckx, E., Albertini, G., Paterka, M., Jensen, C., Albrecht, P., Dietrich, M., Van Liefferinge, J., Bentea, E., Verbruggen, L., Demuyser, T., Deneyer, L., Lewerenz, J., van Loo, G., De Keyser, J., Sato, H., Maher, P., Methner, A., Massie, A. Absence of system xc(-) on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis. (2017) Journal of Neuroinflammation. 14(1):9. DOI: 10.1186/s12974-016-0787-0

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Currais, A., Fischer, W., Maher, P., Schubert, D. Intraneuronal protein aggregation as a trigger for inflammation and neurodegeneration in the aging brain. (2017) FASEB Journal. 31(1):5-10. DOI: 10.1096/fj.201601184

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Currais, A., Quehenberger, O., M Armando, A., Daugherty, D., Maher, P., Schubert, D. Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids. (2016) NPJ Aging and Mechanisms of Disease. 2:16012. DOI: 10.1038/npjamd.2016.12

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Mori, S., Maher, P., Conti, B. Neuroimmunology of the Interleukins 13 and 4. (2016) Brain Sci. 6(2). DOI: 10.3390/brainsci6020018

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Currais, A., Farrokhi, C., Dargusch, R., Goujon-Svrzic, M., Maher, P. Dietary glycemic index modulates the behavioral and biochemical abnormalities associated with autism spectrum disorder. (2016) Molecular Psychiatry. 21(3):426-36. DOI: 10.1038/mp.2015.64

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McClatchy, D.B., Savas, J.N., Martínez-Bartolomé, S., Park, S.K., Maher, P., Powell, S.B., Yates, J.R. Global quantitative analysis of phosphorylation underlying phencyclidine signaling and sensorimotor gating in the prefrontal cortex. (2016) Molecular Psychiatry. 21(2):205-15. DOI: 10.1038/mp.2015.41

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Lewerenz, J., Maher, P. Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence? (2015) Frontiers in Neuroscience. 9:469. DOI: 10.3389/fnins.2015.00469

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Dafre, A.L., Goldberg, J., Wang, T., Spiegel, D.A., Maher, P. Methylglyoxal, the foe and friend of glyoxalase and Trx/TrxR systems in HT22 nerve cells. (2015) Free Radical Biology & Medicine. 89:8-19. DOI: 10.1016/j.freeradbiomed.2015.07.005

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Currais, A., Goldberg, J., Farrokhi, C., Chang, M., Prior, M., Dargusch, R., Daugherty, D., Armando, A., Quehenberger, O., Maher, P., Schubert, D. A comprehensive multiomics approach toward understanding the relationship between aging and dementia. (2015) Aging. 7(11):937-55. DOI: 10.18632/aging.100838

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Krasieva, T.B., Ehren, J., O'Sullivan, T., Tromberg, B.J., Maher, P. Cell and brain tissue imaging of the flavonoid fisetin using label-free two-photon microscopy. (2015) Neurochem. Int. 89:243-8. DOI: 10.1016/j.neuint.2015.08.003

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Maher, P. How fisetin reduces the impact of age and disease on CNS function. (2015) Frontiers in Bioscience. 7:58-82.

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Maher, P., Kontoghiorghes, G.J. Characterization of the neuroprotective potential of derivatives of the iron chelating drug deferiprone. (2015) Neurochemical Research. 40(3):609-20. DOI: 10.1007/s11064-014-1508-7

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Currais, A., Chiruta, C., Goujon-Svrzic, M., Costa, G., Santos, T., Batista, M.T., Paiva, J., do Céu Madureira, M., Maher, P. Screening and identification of neuroprotective compounds relevant to Alzheimer׳s disease from medicinal plants of S. Tomé e Príncipe. (2014) Journal of Ethnopharmacology. 155(1):830-40. DOI: 10.1016/j.jep.2014.06.046

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Prior, M., Chiruta, C., Currais, A., Goldberg, J., Ramsey, J., Dargusch, R., Maher, P.A., Schubert, D. Back to the future with phenotypic screening. (2014) ACS Chem Neurosci. 5(7):503-13. DOI: 10.1021/cn500051h

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Currais, A., Prior, M., Dargusch, R., Armando, A., Ehren, J., Schubert, D., Quehenberger, O., Maher, P. Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice. (2014) Aging Cell. 13(2):379-90. DOI: 10.1111/acel.12185

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Maher, P. Proteasome Assay in Cell Lysates. (2014) Bio Protocol. 4(2).

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Currais, A., Maher, P. Functional consequences of age-dependent changes in glutathione status in the brain. (2013) Antioxid. Redox Signal. 19(8):813-22. DOI: 10.1089/ars.2012.4996

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Valera, E., Dargusch, R., Maher, P.A., Schubert, D. Modulation of 5-lipoxygenase in proteotoxicity and Alzheimer's disease. (2013) Journal of Neuroscience. 33(25):10512-25. DOI: 10.1523/JNEUROSCI.5183-12.2013

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Ehren, J.L., Maher, P. Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. (2013) Biochem. Pharmacol. 85(12):1816-26. DOI: 10.1016/j.bcp.2013.04.010

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Currais, A., Prior, M., Lo, D., Jolivalt, C., Schubert, D., Maher, P. Diabetes exacerbates amyloid and neurovascular pathology in aging-accelerated mice. (2012) Aging Cell. 11(6):1017-26. DOI: 10.1111/acel.12002

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Schubert, D., Maher, P. An alternative approach to drug discovery for Alzheimer's disease dementia. (2012) Future Medicinal Chemistry. 4(13):1681-8. DOI: 10.4155/fmc.12.109

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Maher, P. Methylglyoxal, advanced glycation end products and autism: is there a connection? (2012) Medical Hypotheses. 78(4):548-52. DOI: 10.1016/j.mehy.2012.01.032

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Autism is a complex and heterogeneous neurodevelopmental disorder of unknown etiology but very likely resulting from both genetic and environmental factors. Recent estimates suggest that it affects 1 in 100-150 individuals in the US. Oxidative stress, inflammation and mitochondrial dysfunction have all been suggested to play key roles in autism and may be linked via alterations in cellular redox homeostasis. The glutathione/glutathione disulfide (GSH/GSSG) redox pair forms the major redox couple in cells and as such plays a critical role in regulating redox-dependent cellular functions. A number of studies have shown that variations in genes involved in GSH metabolism are associated with autism. GSH also modulates the activity of glyoxalase 1 (Glo-1), the rate-limiting enzyme for the removal of reactive dicarbonyls such as methylglyoxal (MG). MG is the major precursor for the formation of advanced glycation end products (AGEs). Both MG and AGEs can induce oxidative stress, inflammation and mitochondrial dysfunction and are implicated in diabetic complications and multiple, age-related neurological diseases. Dietary consumption of AGEs and MG correlates with food intake which has increased 20-30% over the past 20 years. Both MG and AGEs are orally absorbed, leading to increased levels in the blood. Furthermore, in humans, increased MG and AGE levels in maternal blood correlate with increased MG and AGE levels in newborn blood, potentially exposing infants to high oxidative stress and inflammation. It is hypothesized that diet derived MG and AGEs in combination with inborn genetic vulnerabilities that affect the cellular redox status are major contributors to the development of autism and provide a causal link between oxidative stress, inflammation and mitochondrial dysfunction. If future research supports this hypothesis, then by reducing the exposure to these diet-derived factors, it might be possible to decrease the prevalence of at least a subset of autism cases.

Chiruta, C., Schubert, D., Dargusch, R., Maher, P. Chemical modification of the multitarget neuroprotective compound fisetin. (2012) Journal of Medicinal Chemistry. 55(1):378-89. DOI: 10.1021/jm2012563

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Chen, Q., Prior, M., Dargusch, R., Roberts, A., Riek, R., Eichmann, C., Chiruta, C., Akaishi, T., Abe, K., Maher, P., Schubert, D. A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease. (2011) PLOS One. 6(12):e27865. DOI: 10.1371/journal.pone.0027865

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Maher, P., Dargusch, R., Ehren, J.L., Okada, S., Sharma, K., Schubert, D. Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes. (2011) PLOS One. 6(6):e21226. DOI: 10.1371/journal.pone.0021226

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Lapchak, P.A., Schubert, D.R., Maher, P.A. De-Risking of Stilbazulenyl Nitrone (STAZN), a Lipophilic Nitrone to Treat Stroke Using a Unique Panel of In Vitro Assays. (2011) Transl Stroke Res. 2(2):209-17. DOI: 10.1007/s12975-011-0071-7

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Maher, P., Dargusch, R., Bodai, L., Gerard, P.E., Purcell, J.M., Marsh, J.L. ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease. (2011) Human Molecular Genetics. 20(2):261-70. DOI: 10.1093/hmg/ddq460

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Lapchak, P.A., Schubert, D.R., Maher, P.A. Delayed treatment with a novel neurotrophic compound reduces behavioral deficits in rabbit ischemic stroke. (2011) J. Neurochem. 116(1):122-31. DOI: 10.1111/j.1471-4159.2010.07090.x

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Maher, P., Akaishi, T., Schubert, D., Abe, K. A pyrazole derivative of curcumin enhances memory. (2010) Neurobiology of Aging. 31(4):706-9. DOI: 10.1016/j.neurobiolaging.2008.05.020

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Maher, P. Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin. (2009) Genes & Nutrition. 4(4):297-307. DOI: 10.1007/s12263-009-0142-5

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Lewerenz, J., Albrecht, P., Tien, M.L., Henke, N., Karumbayaram, S., Kornblum, H.I., Wiedau-Pazos, M., Schubert, D., Maher, P., Methner, A. Induction of Nrf2 and xCT are involved in the action of the neuroprotective antibiotic ceftriaxone in vitro. (2009) J. Neurochem. 111(2):332-43. DOI: 10.1111/j.1471-4159.2009.06347.x

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Herrera, F., Chen, Q., Fischer, W.H., Maher, P., Schubert, D.R. Synaptojanin-1 plays a key role in astrogliogenesis: possible relevance for Down's syndrome. (2009) Cell Death and Differentiation. 16(6):910-20. DOI: 10.1038/cdd.2009.24

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Maher, P.A., Schubert, D.R. Metabolic links between diabetes and Alzheimer's disease. (2009) Expert Rev Neurother. 9(5):617-30. DOI: 10.1586/ern.09.18

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Schubert, D., Herrera, F., Cumming, R., Read, J., Low, W., Maher, P., Fischer, W.H. Neural cells secrete a unique repertoire of proteins. (2009) J. Neurochem. 109(2):427-35. DOI: 10.1111/j.1471-4159.2009.05968.x

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Lewerenz, J., Maher, P. Basal levels of eIF2alpha phosphorylation determine cellular antioxidant status by regulating ATF4 and xCT expression. (2009) Journal of Biological Chemistry. 284(2):1106-15. DOI: 10.1074/jbc.M807325200

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Maher, P., Lewerenz, J., Lozano, C., Torres, J.L. A novel approach to enhancing cellular glutathione levels. (2008) J. Neurochem. 107(3):690-700. DOI: 10.1111/j.1471-4159.2008.05620.x

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Maher, P. The flavonoid fisetin promotes nerve cell survival from trophic factor withdrawal by enhancement of proteasome activity. (2008) Arch. Biochem. Biophys. 476(2):139-44. DOI: 10.1016/j.abb.2008.03.023

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Maher, P. Proteasome inhibitors prevent oxidative stress-induced nerve cell death by a novel mechanism. (2008) Biochem. Pharmacol. 75(10):1994-2006. DOI: 10.1016/j.bcp.2008.02.008

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Liu, Y., Dargusch, R., Maher, P., Schubert, D. A broadly neuroprotective derivative of curcumin. (2008) J. Neurochem. 105(4):1336-45. DOI: 10.1111/j.1471-4159.2008.05236.x

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Maher, P., Hanneken, A. Flavonoids protect retinal ganglion cells from ischemia in vitro. (2008) Experimental Eye Research. 86(2):366-74. DOI: 10.1016/j.exer.2007.11.009

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Burdo, J., Schubert, D., Maher, P. Glutathione production is regulated via distinct pathways in stressed and non-stressed cortical neurons. (2008) Brain Research. 1189:12-22. DOI: 10.1016/j.brainres.2007.10.077

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Lapchak, P.A., Maher, P., Schubert, D., Zivin, J.A. Baicalein, an antioxidant 12/15-lipoxygenase inhibitor improves clinical rating scores following multiple infarct embolic strokes. (2007) Neuroscience. 150(3):585-91. DOI: 10.1016/j.neuroscience.2007.09.033

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Maher, P., Salgado, K.F., Zivin, J.A., Lapchak, P.A. A novel approach to screening for new neuroprotective compounds for the treatment of stroke. (2007) Brain Research. 1173:117-25. DOI: 10.1016/j.brainres.2007.07.061

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Maher, P. Redox control of neural function: background, mechanisms, and significance. (2006) Antioxid. Redox Signal. 8(11-12):1941-70. DOI: 10.1089/ars.2006.8.1941

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Maher, P., Akaishi, T., Abe, K. Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. (2006) Proceedings of the National Academy of Sciences of the United States of America. 103(44):16568-73. DOI: 10.1073/pnas.0607822103

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Maher, P. A comparison of the neurotrophic activities of the flavonoid fisetin and some of its derivatives. (2006) Free Radic. Res. 40(10):1105-11. DOI: 10.1080/10715760600672509

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Maher, P., Hanneken, A. Flavonoids protect retinal ganglion cells from oxidative stress-induced death. (2005) Investigative Ophthalmology & Visual Science. 46(12):4796-803. DOI: 10.1167/iovs.05-0397

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Maher, P. The effects of stress and aging on glutathione metabolism. (2005) Ageing Research Reviews. 4(2):288-314. DOI: 10.1016/j.arr.2005.02.005

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Conti, B., Sugama, S., Lucero, J., Winsky-Sommerer, R., Wirz, S.A., Maher, P., Andrews, Z., Barr, A.M., Morale, M.C., Paneda, C., Pemberton, J., Gaidarova, S., Behrens, M.M., Beal, F., Sanna, P.P., Horvath, T., Bartfai, T. Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6-methyl-phenyl-tetrahydropyridine toxicity. (2005) Journal of Neurochemistry. 93(2):493-501. DOI: 10.1111/j.1471-4159.2005.03052.x

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Maher, P., Hanneken, A. The molecular basis of oxidative stress-induced cell death in an immortalized retinal ganglion cell line. (2005) Investigative Ophthalmology & Visual Science. 46(2):749-57. DOI: 10.1167/iovs.04-0883

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Soucek, T., Cumming, R., Dargusch, R., Maher, P., Schubert, D. The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide. (2003) Neuron. 39(1):43-56. DOI: 10.1016/s0896-6273(03)00367-2

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Tan, S., Schubert, D., Maher, P. Oxytosis: A novel form of programmed cell death. (2001) Current Topics in Medicinal Chemistry. 1(6):497-506.

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Chen, Q., Yoshida, H., Schubert, D., Maher, P., Mallory, M., Masliah, E. Presenilin binding protein is associated with neurofibrillary alterations in Alzheimer's disease and stimulates tau phosphorylation. (2001) Am. J. Pathol. 159(5):1597-602. DOI: 10.1016/S0002-9440(10)63005-2

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Tan, S., Somia, N., Maher, P., Schubert, D. Regulation of antioxidant metabolism by translation initiation factor 2alpha. (2001) Journal of Cell Biology. 152(5):997-1006.

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Maher, P., Schubert, D. Signaling by reactive oxygen species in the nervous system. (2000) Cellular and Molecular Life Sciences. 57(8-9):1287-305.

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Sagara, Y., Dargusch, R., Chambers, D., Davis, J., Schubert, D., Maher, P. Cellular mechanisms of resistance to chronic oxidative stress. (1998) Free Radical Biology & Medicine. 24(9):1375-89.

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Tan, S., Sagara, Y., Liu, Y., Maher, P., Schubert, D. The regulation of reactive oxygen species production during programmed cell death. (1998) Journal of Cell Biology. 141(6):1423-32.

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Li, Y., Maher, P., Schubert, D. Phosphatidylcholine-specific phospholipase C regulates glutamate-induced nerve cell death. (1998) Proceedings of the National Academy of Sciences of the United States of America. 95(13):7748-53. DOI: 10.1073/pnas.95.13.7748

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Sagara, Y., Tan, S., Maher, P., Schubert, D. Mechanisms of resistance to oxidative stress in Alzheimer's disease. (1998) Biofactors. 8(1-2):45-50.

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Li, Y., Maher, P., Schubert, D. Requirement for cGMP in nerve cell death caused by glutathione depletion. (1997) Journal of Cell Biology. 139(5):1317-24.

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Tan, S., Maher, P., Schubert, D. The role of protein phosphorylation in beta amyloid toxicity. (1997) Brain Research. 765(1):159-63.

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Li, Y., Maher, P., Schubert, D. A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. (1997) Neuron. 19(2):453-63.

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Davis, J.B., Maher, P. Protein kinase C activation inhibits glutamate-induced cytotoxicity in a neuronal cell line. (1994) Brain Research. 652(1):169-73. DOI: 10.1016/0006-8993(94)90334-4

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Schubert, D., Kimura, H., Maher, P. Growth factors and vitamin E modify neuronal glutamate toxicity. (1992) Proceedings of the National Academy of Sciences of the United States of America. 89(17):8264-7.

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Pamela Maher, PhD

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