Life Sciences Commons^™

Aibp Regulates Trpv1 Activation In Chemotherapy-Induced Peripheral Neuropathy By Controlling Lipid Raft Dynamics And Proximity To Tlr4 In Dorsal Root Ganglion Neurons, Juliana M Navia-Pelaez, Julia Borges Paes Lemes, Leonardo Gonzalez, Lauriane Delay, Luciano Dos Santos Aggum Capettini, Jenny W Lu, Gilson Gonçalves Dos Santos, Ann M Gregus, Patrick M Dougherty, Tony L Yaksh, Yury I Miller

Student and Faculty Publications

Nociceptive afferent signaling evoked by inflammation and nerve injury is mediated by the opening of ligand-gated and voltage-gated receptors or channels localized to cholesterol-rich lipid raft membrane domains. Dorsal root ganglion (DRG) nociceptors express high levels of toll-like receptor 4 (TLR4), which also localize to lipid rafts. Genetic deletion or pharmacologic blocking of TLR4 diminishes pain associated with chemotherapy-induced peripheral neuropathy (CIPN). In DRGs of mice with paclitaxel-induced CIPN, we analyzed DRG neuronal lipid rafts, expression of TLR4, activation of transient receptor potential cation channel subfamily V member 1 (TRPV1), and TLR4-TRPV1 interaction. Using proximity ligation assay, flow cytometry, and …

Resolution Of Cisplatin-Induced Fatigue Does Not Require Endogenous Interleukin-10 In Male Miceb, Kiersten Scott, Nabila Boukelmoune, Cullen Taniguchi, A Phillip West, Cobi J Heijnen, Robert Dantzer

Student and Faculty Publications

Based on previous results showing a pivotal role of endogenous interleukin-10 (IL-10) in the recovery from cisplatin-induced peripheral neuropathy, the present experiments were carried out to determine whether this cytokine plays any role in the recovery from cisplatin-induced fatigue in male mice. Fatigue was measured by decreased voluntary wheel running in mice trained to run in a wheel in response to cisplatin. Mice were treated with a monoclonal neutralizing antibody (IL-10na) administered intranasally during the recovery period to neutralize endogenous IL-10. In the first experiment, mice were treated with cisplatin (2.83 mg/kg/day) for five days and IL-10na (12 μg/day for …

Hdac2 In Primary Sensory Neurons Constitutively Restrains Chronic Pain By Repressing Α2Δ-1 Expression And Associated Nmda Receptor Activity, Jixiang Zhang, Shao-Rui Chen, Meng-Hua Zhou, Daozhong Jin, Hong Chen, Li Wang, Ronald A Depinho, Hui-Lin Pan

Student and Faculty Publications

α2δ-1 (encoded by the Cacna2d1 gene) is a newly discovered NMDA receptor-interacting protein and is the therapeutic target of gabapentinoids (e.g., gabapentin and pregabalin) frequently used for treating patients with neuropathic pain. Nerve injury causes sustained α2δ-1 upregulation in the dorsal root ganglion (DRG), which promotes NMDA receptor synaptic trafficking and activation in the spinal dorsal horn, a hallmark of chronic neuropathic pain. However, little is known about how nerve injury initiates and maintains the high expression level of α2δ-1 to sustain chronic pain. Here, we show that nerve injury caused histone hyperacetylation and diminished enrichment of histone deacetylase-2 (HDAC2), …

Loss Of Lamp5 Interneurons Drives Neuronal Network Dysfunction In Alzheimer’S Disease, Yuanyuan Deng, Mian Bi, Fabien Delerue, Shelley L Forrest, Gabriella Chan, Julia Van Der Hoven, Annika Van Hummel, Astrid F Feiten, Seojin Lee, Ivan Martinez-Valbuena, Tim Karl, Gabor G Kovacs, Grant Morahan, Yazi D Ke, Lars M Ittner

Student and Faculty Publications

In Alzheimer's disease (AD), where amyloid-β (Aβ) and tau deposits in the brain, hyperexcitation of neuronal networks is an underlying disease mechanism, but its cause remains unclear. Here, we used the Collaborative Cross (CC) forward genetics mouse platform to identify modifier genes of neuronal hyperexcitation. We found LAMP5 as a novel regulator of hyperexcitation in mice, critical for the survival of distinct interneuron populations. Interestingly, synaptic LAMP5 was lost in AD brains and LAMP5 interneurons degenerated in different AD mouse models. Genetic reduction of LAMP5 augmented functional deficits and neuronal network hypersynchronicity in both Aβ- and tau-driven AD mouse models. …

Par2 (Protease-Activated Receptor 2) Deficiency Attenuates Atherosclerosis In Mice, Shannon M. Jones, Adrien Mann, Kelsey Conrad, Keith Saum, David E. Hall, Lisa M. Mckinney, Nathan Robbins, Joel Thompson, Abigail D. Peairs, Eric Camerer, Katey J. Rayner, Michael Tranter, Nigel Mackman, A. Phillip Owens

Exercise and Sport Studies: Faculty Publications

Objective-PAR2 (protease-activated receptor 2)-dependent signaling results in augmented inflammation and has been implicated in the pathogenesis of several autoimmune conditions. The objective of this study was to determine the effect of PAR2 deficiency on the development of atherosclerosis. Approach and Resutle-PAR2 mRNA and protein expression is increased in human carotid artery and mouse aortic arch atheroma versus control carotid and aortic arch arteries, respectively. To determine the effect of PAR2 deficiency on atherosclerosis, male and female low-density lipoprotein receptor-deficient (Ldlr-/-) mice (8-12 weeks old) that were Par2+/+ or Par2-/- were fed a fat-and cholesterol-enriched diet for 12 or 24 weeks. …

Single-Trait And Multi-Trait Genome-Wide Association Analyses Identify Novel Loci For Blood Pressure In African-Ancestry Populations, Jingjing Liang, Thu H. Le, Digna R. Velez Edwards, Bamidele O. Tayo, Kyle J. Gaulton, Jennifer A. Smith, Yingchang Lu, Richard A. Jensen, Guanjie Chen, Lisa R. Yanek, Karen Schwander, Salman M. Tajuddin, Tamar Sofer, Wonji Kim, James Kayima, Colin A. Mckenzie, Ervin Fox, Michael A. Nalls, J. Hunter Young, Yan V. Sun, Jacqueline M. Lane, Sylvia Cechova, Jie Zhou, Hua Tang, Myriam Fornage, Solomon K. Musani, Heming Wang, Juyoung Lee, Adebowale Adeyemo, Albert W. Dreisbach, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10⁻⁸) for either systolic and …

Retention Of Normal Glia Function By An Isoform-Selective Protein Kinase Inhibitor Drug Candidate That Modulates Cytokine Production And Cognitive Outcomes, Zhengqiu Zhou, Adam D. Bachstetter, Claudia B. Späni, Saktimayee M. Roy, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Background: Brain p38α mitogen-activated protein kinase (MAPK), a potential therapeutic target for cognitive dysfunction based on the neuroinflammation-synaptic dysfunction cycle of pathophysiology progression, offers an innovative pharmacological strategy via inhibiting the same activated target in both glia and neurons, thereby enhancing the possibility for efficacy. The highly selective, brain-penetrant p38αMAPK inhibitor MW150 attenuates cognitive dysfunction in two distinct Alzheimer's disease (AD)-relevant models and avoids the problems encountered with previous mixed-kinase inhibitor drug candidates. Therefore, it is essential that the glial effects of this CNS-active kinase inhibitor be addressed in order to anticipate future use in clinical investigations.

Methods: …

Selective Suppression Of The Α Isoform Of P38 Mapk Rescues Late-Stage Tau Pathology, Nicole Maphis, Shanya Jiang, Guixiang Xu, Olga N. Kokiko-Cochran, Saktimayee M. Roy, Linda J. Van Eldik, D. Martin Watterson, Bruce T. Lamb, Kiran Bhaskar

Sanders-Brown Center on Aging Faculty Publications

Background: Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer’s disease and related tauopathies. We previously demonstrated that the microglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 mitogen-activated protein kinase (p38 MAPK) in the hTau mouse model of tauopathy that was deficient for microglial fractalkine receptor CX3CR1.

Method: We report an isoform-selective, brain-permeable, and orally bioavailable small molecule inhibitor of p38α MAPK (MW181) and its effects on tau phosphorylation in vitro and in hTau mice.

Results: First, pretreatment of mouse primary cortical neurons with MW181 completely blocked inflammation-induced p38α MAPK activation and AT8 …

Reduced Efficacy Of Anti-AΒ Immunotherapy In A Mouse Model Of Amyloid Deposition And Vascular Cognitive Impairment Comorbidity, Erica M. Weekman, Tiffany L. Sudduth, Carly N. Caverly, Timothy J. Kopper, Oliver W. Phillips, David K. Powell, Donna M. Wilcock

Sanders-Brown Center on Aging Faculty Publications

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain. While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID …

Mw151 Inhibited Il-1Β Levels After Traumatic Brain Injury With No Effect On Microglia Physiological Responses, Adam D. Bachstetter, Zhengqiu Zhou, Rachel K. Rowe, Bin Xing, Danielle S. Goulding, Alyssa N. Conley, Pradoldej Sompol, Shelby Meier, Jose F. Abisambra, Jonathan Lifshitz, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

A prevailing neuroinflammation hypothesis is that increased production of proinflammatory cytokines contributes to progressive neuropathology, secondary to the primary damage caused by a traumatic brain injury (TBI). In support of the hypothesis, post-injury interventions that inhibit the proinflammatory cytokine surge can attenuate the progressive pathology. However, other post-injury neuroinflammatory responses are key to endogenous recovery responses. Therefore, it is critical that pharmacological attenuation of detrimental or dysregulated neuroinflammatory processes avoid pan-suppression of inflammation. MW151 is a CNS-penetrant, small molecule experimental therapeutic that restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis without immunosuppression. Post-injury administration of MW151 in a …

It Is All About (U)Biquitin: Role Of Altered Ubiquitin-Proteasome System And Uchl1 In Alzheimer Disease, Antonella Tramutola, Fabio Di Domenico, Eugenio Barone, Marzia Perluigi, D. Allan Butterfield

Chemistry Faculty Publications

Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased efficiency …

Transmembrane Domain Nrg1 Mutant Mice Show Altered Susceptibility To The Neurobehavioural Actions Of Repeated Thc Exposure In Adolescence, Leonora E. Long, Rose Chesworth, Xu-Feng Huang, Iain S. Mcgregor, Jonathon C. Arnold, Tim Karl

Faculty of Health and Behavioural Sciences - Papers (Archive)

Heavy cannabis abuse increases the risk of developing schizophrenia. Adolescents appear particularly vulnerable to the development of psychosis-like symptoms after cannabis use. To test whether the schizophrenia candidate gene neuregulin 1 (NRG1) modulates the effects of cannabinoids in adolescence, we tested male adolescent heterozygous transmembrane domain Nrg1 mutant (Nrg1 TM HET) mice and wild type-like littermates (WT) for their neurobehavioural response to repeated Δ⁹-tetrahydrocannabinol (THC, 10 mg/kg i.p. for 21 d starting on post-natal day 31). During treatment and 48 h after treatment withdrawal, we assessed several behavioural parameters relevant to schizophrenia. After behavioural testing we measured autoradiographic …

Prolonged Pain Research In Mice: Trends In Reference To The 3rs, Jonathan Balcombe, Hope Ferdowsian, Lauren Briese

Experimentation Collection

This literature review documents trends in the use of mice in prolonged pain research, defined herein as research that subjects mice to a source of pain for at least 14 days. The total amount of prolonged pain research on mice has increased dramatically in the past decade for the 3 pain categories examined: neuropathic, inflammatory, and chronic pain. There has also been a significant rise in the number of prolonged mouse pain studies as a proportion of all mouse studies and of all mouse pain studies. The use of transgenic mice has also risen significantly in prolonged pain research, though …

Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction In A Mouse Model That Exhibits Age-Dependent Progression Of Alzheimer's Disease-Related Pathology, Adam D. Bachstetter, Christopher M. Norris, Pradoldej Sompol, Donna M. Wilcock, Danielle Goulding, Janna H. Neltner, Daret St. Clair, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Overproduction of proinflammatory cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer's disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial proinflammatory cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial proinflammatory cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that …

Metabolic Parameters And Emotionality Are Little Affected In G-Protein Coupled Receptor 12 (Gpr12) Mutant Mice, Elisabeth Frank, Yizhen Wu, Naomi Piyaratna, William James Body, P Snikeris, Timothy South, Anna-Karin Gerdin, Mikael Bjursell, Mohammad Bohlooly-Y, Leonard H. Storlien, Xu-Feng Huang

Faculty of Health and Behavioural Sciences - Papers (Archive)

Background: G-protein coupled receptors (GPR) bear the potential to serve as yet unidentified drug targets for psychiatric and metabolic disorders. GPR12 is of major interest given its putative role in metabolic function and its unique brain distribution, which suggests a role in emotionality and affect. We tested Gpr12 deficient mice in a series of metabolic and behavioural tests and subjected them to a well-established high-fat diet feeding protocol. Methodology/Principal Findings: Comparing the mutant mice with wild type littermates, no significant differences were seen in body weight, fatness or weight gain induced by a high-fat diet. The Gpr12 mutant mice displayed …

Toward Genuine Rodent Welfare: Response To Reviewer Comments, Jonathan P. Balcombe

Laboratory Experiments Collection

I’m grateful to the editors for soliciting critiques of my commentary and for the opportunity to respond. Because one of the respondents (Patterson-Kane, 2010/this issue) does not take issue with the main points of my article, whereas the other (Blanchard, 2010/this issue) does, I focus my remarks here mostly on Blanchard’s critique.

Laboratory Rodent Welfare: Thinking Outside The Cage, Jonathan P. Balcombe

Laboratory Experiments Collection

This commentary presents the case against housing rats and mice in laboratory cages; the commentary bases its case on their sentience, natural history, and the varied detriments of laboratory conditions. The commentary gives 5 arguments to support this position: (a) rats and mice have a high degree of sentience and can suffer, (b) laboratory environments cause suffering, (c) rats and mice in the wild have discrete behavioral needs, (d) rats and mice bred for many generations in the laboratory retain these needs, and (e) these needs are not met in laboratory cages.

A Behavioural Comparison Of Acute And Chronic Δ9-Tetrahydrocannabinol And Cannabidiol In C57bl/6jarc Mice, Ian Mcgregor, Xu-Feng Huang, Tim Karl, Jonathon Arnold, Rose Chesworth, Leonora E. Long

Faculty of Health and Behavioural Sciences - Papers (Archive)

Cannabis contains over 70 unique compounds and its abuse is linked to an increased risk of developing schizophrenia. The behavioural profiles of the psychotropic cannabis constituent Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and the non-psychotomimetic constituent cannabidiol (CBD) were investigated with a battery of behavioural tests relevant to anxiety and positive, negative and cognitive symptoms of schizophrenia. Male adult C57BL/6JArc mice were given 21 daily intraperitoneal injections of vehicle, Δ⁹-THC (0.3, 1, 3 or 10 mg/kg) or CBD (1, 5, 10 or 50 mg/kg). Δ⁹-THC produced the classic cannabinoid CB₁ receptor-mediated tetrad of hypolocomotion, analgesia, …

Limitations On Spatial Memory In Mice, Robert H.I. Dale, Martin Bedard

Scholarship and Professional Work - LAS

Rats have an impressive ability to remember locations they have visited. Two experiments used an eight-arm radial maze to determine whether mice showed two important characteristics of this spatial memory: its durability, and its dependence on stimuli outside the maze (extreme stimuli). In Experiment 1, food-deprived mice were allowed to eat from four of the eight arms of the maze then, after delays of 5 sec, 1 min, or 5 min, they were permitted to choose the remaining arms. Choice accuracy declined significantly with the longer delays, but always remained above chance. In Experiment 2, the maze was rotated 180° …