Browsing by Author "Wilson, Sarah M."

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    Identification of a functional interaction of HMGB1 with Receptor for Advanced Glycation End-products in a model of neuropathic pain
    (Elsevier, 2014-11) Allette, Yohance M.; Due, Michael R.; Wilson, Sarah M.; Feldman, Polina; Ripsch, Matthew S.; Khanna, Rajesh; White, Fletcher A.; Department of Anesthesia, IU School of Medicine
    Recent studies indicate that the release of high mobility group box 1 (HMGB1) following nerve injury may play a central role in the pathogenesis of neuropathic pain. HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End-products (RAGE) and Toll-like receptors (TLRs). The degree to which HMGB1 activates a receptor is thought to be dependent upon the oxidative state of the ligand, resulting in the functional isoforms of all-thiol HMGB1 (at-HMGB1) acting through RAGE, and disufide HMGB1 (ds-HMGB1) interacting with TLR4. Though it is known that dorsal root ganglia (DRG) sensory neurons exposed to HMGB1 and TLR4 agonists can influence excitation, the degree to which at-HMGB1 signaling through neuronal RAGE contributes to neuropathic pain is unknown. Here we demonstrate that at-HMGB1 activation of nociceptive neurons is dependent on RAGE and not TLR4. To distinguish the possible role of RAGE on neuropathic pain, we characterized the changes in RAGE mRNA expression up to one month after tibial nerve injury (TNI). RAGE mRNA expression in lumbar dorsal root ganglion (DRG) is substantially increased by post-injury day (PID) 28 when compared with sham injured rodents. Protein expression at PID28 confirms this injury-induced event in the DRG. Moreover, a single exposure to monoclonal antibody to RAGE (RAGE Ab) failed to abrogate pain behavior at PID 7, 14 and 21. However, RAGE Ab administration produced reversal of mechanical hyperalgesia on PID28. Thus, at-HMGB1 activation through RAGE may be responsible for sensory neuron sensitization and mechanical hyperalgesia associated with chronic neuropathic pain states.
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    The Role of Sex-Related Alcohol Expectancies in Alcohol-Involved Consensual and Nonconsensual Sex Among Women of Asian/Pacific Islander and Women of European Race/Ethnicity
    (Taylor & Francis, 2018-09) Dier, Allyson L.; Andrews III, Arthur R.; Wilson, Sarah M.; Davidson, Tatiana M.; Gilmore, Amanda K.; Family Medicine, School of Medicine
    Alcohol-involved sexual experiences, including incapacitated sexual assault and alcohol-involved sex, are major public health concerns among college women. Further, racial/ethnic diversity among college students is increasing, particularly with regard to increases in college students of Asian/Pacific Islander (API) race/ethnicity. Of relevance, evidence suggests differences in sexual assault rates across ethnicities and cultures; however, no known study to date has examined differences by ethnicity and first language in expectancies and experiences specifically surrounding alcohol and sex. The current study sought to examine differences in incapacitated sexual assault, alcohol-involved sex, and heavy episodic drinking, as well as differences in sex-related alcohol expectancies among native English-speaking college women of European (EU) race/ethnicity, native English-speaking women of API race/ethnicity, and non-native English-speaking women of API race/ethnicity (NNES-API). EU reported higher frequency of heavy episodic drinking, alcohol-involved sex, and incapacitated sexual assault compared to API and NNES-API. In addition, API reported more frequent alcohol-involved sex and incapacitated sexual assault compared to NNES-API, in part due to API's stronger endorsement of sexual disinhibition-related alcohol expectancies (indirect effects: β = -.04, p = .04, and β = -.07, p = .04, respectively). Findings highlight the important role of expectancies in acculturation and influence on actual alcohol-involved sex and sexual assault.
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    Specific binding of lacosamide to collapsin response mediator protein 2 (CRMP2) and direct impairment of its canonical function: implications for the therapeutic potential of lacosamide
    (Springer-Verlag, 2015-04) Wilson, Sarah M.; Khanna, Rajesh; Department of Pharmacology and Toxicology, IU School of Medicine
    The novel antiepileptic drug lacosamide (LCM; SPM927, Vimpat®) has been heralded as having a dual-mode of action through interactions with both the voltage-gated sodium channel and the neurite outgrowth-promoting collapsin response mediator protein 2 (CRMP2). Lacosamide's ability to dampen neuronal excitability through the voltage-gated sodium channel likely underlies its efficacy in attenuating the symptoms of epilepsy (i.e., seizures). While the role of CRMP2 in epilepsy has not been well studied, given the proposed involvement of circuit reorganization in epileptogenesis, the ability of lacosamide to alter CRMP2 function may prove disease modifying. Recently, however, the validity of lacosamide's interaction with CRMP2 has come under scrutiny. In this review, we address the contradictory reports concerning the binding of lacosamide to CRMP2 as well as the ability of lacosamide to directly impact CRMP2 function. Additionally, we address similarly the contradicting reports regarding the potential disease-modifying effect of lacosamide on the development and progression of epilepsy. As the vast majority of antiepileptic drugs influences only the symptoms of epilepsy, the ability to hinder disease progression would be a major breakthrough in efforts to cure or prevent this debilitating syndrome.
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    Substituted N-(Biphenyl-4′-yl)methyl (R)-2-Acetamido-3-methoxypropionamides: Potent Anticonvulsants That Affect Frequency (Use) Dependence and Slow Inactivation of Sodium Channels
    (American Chemical Society, 2014-07-24) Lee, Hyosung; Park, Ki Duk; Torregrosa, Robert; Yang, Xiao-Fang; Dustrude, Erik T.; Wang, Yuying; Wilson, Sarah M.; Barbosa, Cindy; Xiao, Yucheng; Cummins, Theodore R.; Khanna, Rajesh; Kohn, Harold; Department of Pharmacology and Toxicology, IU School of Medicine
    , We prepared 13 derivatives of N-(biphenyl-4′-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound’s whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI = TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.
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    Tlx3 promotes glutamatergic neuronal subtype specification through direct interactions with the chromatin modifier CBP
    (Public Library of Science, 2015) Shimomura, Atsushi; Patel, Dharmeshkumar; Wilson, Sarah M.; Koehler, Karl R.; Khanna, Rajesh; Hashino, Eri; Department of Otolaryngology Head and Neck Surgery, IU School of Medicine
    Nervous system development relies on the generation of precise numbers of excitatory and inhibitory neurons. The homeodomain transcription factor, T-cell leukemia 3 (Tlx3), functions as the master neuronal fate regulator by instructively promoting the specification of glutamatergic excitatory neurons and suppressing the specification of gamma-aminobutyric acid (GABAergic) neurons. However, how Tlx3 promotes glutamatergic neuronal subtype specification is poorly understood. In this study, we found that Tlx3 directly interacts with the epigenetic co-activator cyclic adenosine monophosphate (cAMP)-response element-binding protein (CREB)-binding protein (CBP) and that the Tlx3 homeodomain is essential for this interaction. The interaction between Tlx3 and CBP was enhanced by the three amino acid loop extension (TALE)-class homeodomain transcription factor, pre-B-cell leukemia transcription factor 3 (Pbx3). Using mouse embryonic stem (ES) cells stably expressing Tlx3, we found that the interaction between Tlx3 and CBP became detectable only after these Tlx3-expressing ES cells were committed to a neural lineage, which coincided with increased Pbx3 expression during neural differentiation from ES cells. Forced expression of mutated Tlx3 lacking the homeodomain in ES cells undergoing neural differentiation resulted in significantly reduced expression of glutamatergic neuronal subtype markers, but had little effect on the expression on pan neural markers. Collectively, our results strongly suggest that functional interplay between Tlx3 and CBP plays a critical role in neuronal subtype specification, providing novel insights into the epigenetic regulatory mechanism that modulates the transcriptional efficacy of a selective set of neuronal subtype-specific genes during differentiation.