Biology subjects

Marriott, A. E.

Publications and source records attributed to Marriott, A. E..

6 recordsLinked to original sources

bioRxiv2025

Impact of early locus coeruleus lesions in the TgF344 Alzheimer's disease rat model

INTRODUCTIONIn murine models of Alzheimers disease (AD), lesioning the locus coeruleus-norepinephrine (LC-NE) system with DSP-4 exacerbates AD-like neuropathology and cognitive impairment. However, the impact of LC lesions during prodromal stages is poorly characterized. METHODSTgF344-AD and wild-type rats received monthly injections of DSP-4 or saline from 1-5 months of age, a time point preceding forebrain plaque or tangle deposition in TgF344-AD rats, after which behavior and pathology were assessed. RESULTSDSP-4 compromised LC cell bodies, fibers, and NE content. LC lesion and the AD transgene each affected several affective behaviors and/or cognition individually, but few interactions were found and DSP-4 failed to exacerbate behavioral phenotypes or neuropathology in TgF344-AD rats. DISCUSSIONCombined with previous literature, our data suggest that LC lesions exacerbate pre-existing AD-like pathology and behavioral impairments, rather than accelerate their onset. Further characterization of LC lesions in TgF344-AD rats at different ages is warranted. Research-in-ContextO_LISystemic review: The authors reviewed existing literature using traditional sources, including PubMed. Previous studies investigated the impact of locus coeruleus (LC) lesions on Alzheimers disease (AD)-like neuropathology and behavior in murine models of AD. However, the impact of LC degeneration in an animal model that expresses both amyloid and endogenous tau pathology at a time point before the emergence of significant forebrain pathology is underexplored. C_LIO_LIInterpretation: We expanded the behavioral and molecular characterization of TgF344-AD rats in response to N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4)-induced LC lesions during the pre-pathology stages of disease. Unexpectedly, we found that TgF344-AD genotype and DSP-4 rarely interacted to exacerbate AD-related symptoms or pathology. C_LIO_LIFuture Directions: Our results indicate LC lesions do not accelerate onset of AD-like neuropathology or behavioral impairment in this model. Future studies in older TgF344-AD animals and using different DSP-4 treatment regimens would help clarify the relationship between LC integrity and AD progression. C_LI HighlightsO_LILocus coeruleus damage causes apathy-like behavior and changes in arousal C_LIO_LITgF344-AD genotype induces social recognition deficits and anxiety-like behavior C_LIO_LILocus coeruleus damage and TgF344-AD genotype rarely interact to worsen deficits C_LIO_LIInteractions that exacerbate Alzheimers disease neuropathology were also scarce C_LI

neuroscience↗

bioRxiv2025

Discovery and Development of DC-174 as a Novel Oral Snakebite Treatment

Snakebite envenoming is a neglected tropical disease that causes high mortality and morbidity. The current treatment, intravenous antivenom, comes with numerous disadvantages making new therapeutics important. Optimised small molecules offer the possibility for oral use at the onset of envenoming, and the highly pathogenic, zinc-dependent, snake venom metalloproteinase toxin family represents an attractive target for drug discovery. Through systematic chemical modification guided by molecular modelling, we describe the development of hydroxamic acid DC-174, a molecule that displays potent broad spectrum metalloproteinase inhibition and neutralises the procoagulant activities of multiple snake venoms. In oral-dosing studies, DC-174 showed preclinical efficacy in a mouse model of severe envenoming, with efficacy boosted by a pharmacokinetically-informed multiple dosing regimen. This rationally designed metalloproteinase inhibitor offers a potential paradigm shift from delayed treatment with antivenom in tertiary hospitals to a contemporary approach using oral drugs amenable for rapid use in snakebite-affected communities.

pharmacology and toxicology↗

bioRxiv2025

A drug combinational therapy consisting of toxin phospholipase A2 and metalloproteinase inhibitors provides preclinical protection against North American Crotalid snakebite envenoming

BackgroundAcross North America an estimated 3,800-6,500 snakebite envenomings occur annually, resulting in 7-15 deaths and an unknown number of disfigurements and disabilities. Most bites are caused by Crotalid snake species. The variable diversity and toxin complexity of crotalid venoms presents a considerable challenge to developing broadly effective small molecule therapeutics to better treat snakebite in this region. MethodsWe evaluated the ability of three small molecule, toxin inhibiting, repurposed drugs to inhibit the venom activities of six medically important crotalid snake species (Agkistrodon contortrix, Crotalus atrox, C. adamanteus, C. horridus, C. scutulatus and Sistrurus miliarius). These drugs target two pathologically relevant venom toxin families, the snake venom metalloproteinases (SVMPs; marimastat and DMPS) and phospholipases A2 (PLA2s; varespladib), and venom inhibition was measured using in vitro enzymatic and phenotypic plasma coagulation assays. Thereafter we evaluated the efficacy of individual drugs and dual drug combinations in in vivo preclinical models of snakebite envenoming, using both preincubation and rescue model formats. ResultsIn vitro bioassays demonstrated that the selected small molecules showed potent inhibition of the enzymatic activity of different toxin families to the nanomolar (varespladib vs PLA2 and marimastat vs SVMP) or micromolar (DMPS vs SVMP) level. Three of the venoms had anticoagulant activity, which varespladib restored to normal coagulation profiles, suggesting this activity is mostly driven by PLA2 toxins. Preclinical experiments revealed that pre-incubation of representative venoms with single drugs was insufficient to completely protect against lethality, except for varespladib against C. scutulatus. Superior efficacy was observed when drugs were used in a combination approach, with the combination of marimastat and varespladib providing greatest protection against lethality in both pre-incubation and rescue models. ConclusionsVenom variation among snake species makes the development of generic snakebite therapeutics challenging. In this study we showed that while SVMP and PLA2 inhibiting drugs show inhibitory potency against diverse North American snake venoms, drug combinations consisting of an SVMP inhibitor together with a PLA2 inhibitor are required to confer broad in vivo protection against lethality caused by envenoming. This study highlights the potential long-term value of drug combinations as next-generation therapeutics for snakebite envenoming.

molecular biology↗

bioRxiv2023

A dirofilariasis mouse model for heartworm preclinical research

Use of experimental cats and dogs in veterinary heartworm preclinical drug research is increasing. As a potential alternative primary in vivo heartworm preventative drug screen, we assessed lymphopenic mice with ablation of the interleukin-2/7 common gamma chain ({gamma}c) as susceptible to the larval development phase of D. immitis. Non-obese diabetic (NOD) Severe Combined ImmunoDeficient (SCID){gamma}c-/-(NSG / NXG) mice consistently yielded viable D. immitis larvae at 2-4 weeks post-infection across multiple experiments, different batches of infectious larvae inoculates, different isolates of D. immitis and at independent laboratories. Mice did not display any overt clinical signs associated with infection up to 4 weeks. Developing larvae were found in subcutaneous and muscle fascia tissues, the natural site of this stage of heartworm in dogs. Larvae retrieved from NSG / NXG mice were mid-L4 stage of development. Compared with 14-day in vitro propagated larvae, in vivo derived L4 were significantly larger and contained expanded Wolbachia endobacteria titres, determined by QPCR and Fluorescent in situ Hybridisation (FISH). We established an ex vivo 6-day L4 paralytic screening system against nematodicidal agents (moxidectin, levamisole) which highlighted discrepancies in relative drug sensitivities in comparison with in vitro reared L4 D. immitis. We demonstrated effective depletion of Wolbachia by 70-90% in D. immitis L4 following 2-7 day oral in vivo exposures of NSG / NXG infected mice with doxycycline or the rapid-acting investigational anti-Wolbachia drug, AWZ1066S. We validated the NSG / NXG mouse model as a filaricide drug screen by in vivo treatments with single injections of moxidectin, which mediated 60-88% reduction in L4 larvae at 14-28 days. Future adoption of the mouse model as a first-line efficacy screen will benefit end-user laboratories conducting research and development of novel heartworm preventatives via increased access, rapid turnaround and reduced costs whilst simultaneously decreasing need for experimental cat or dog use.

microbiology↗

bioRxiv2020

Structural requirements for dihydrobenzoxazepinone anthelmintics: actions against medically important and model parasites - Trichuris muris, Brugia malayi and Heligmosomoides polygyrus

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from Trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority, and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesised 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action, as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQ) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics. Author summaryAround a billion people are infected by the soil transmitted helminths Ascaris, hookworm and whipworm. In the case of whipworm, the benzimidazole drugs, which are distributed to school children in affected areas, have low cure rates. This means that finding an improved treatment for whipworm is a priority. We previously identified five DHB compounds in a screen for new compounds active against whipworm. Here we systematically dissect these molecules, making 47 modified versions of the compounds. This allowed us to define the features of these compounds that are important for activity against whipworm. We also demonstrate activity of DHB compounds against other parasitic nematodes, and against Schistosoma mansoni, a trematode parasite. These results show the potential for further development of DHB compounds as broad-spectrum anthelmintics.

pharmacology and toxicology↗

bioRxiv2020

Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19.

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2, a recently emerged coronavirus that rapidly caused a pandemic. Coalescence of this virus with seasonal respiratory viruses, particularly influenza virus is a global health concern. To investigate this, transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) were first infected with IAV followed by SARS-CoV-2. The host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 only. Infection of mice with each individual virus resulted in a disease phenotype compared to control mice. Although SARS-CoV-2 RNA synthesis appeared significantly reduced in the sequentially infected mice, they exhibited more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to singly infected or control mice. The sequential infection also exacerbated the extrapulmonary encephalitic manifestations associated with SARS-CoV-2 infection. Conversely, prior infection with a commercially available, multivalent live-attenuated influenza vaccine (Fluenz tetra) elicited the same reduction in SARS-CoV-2 RNA synthesis albeit without the associated increase in disease severity. This suggests that the innate immune response stimulated by infection with IAV is responsible for the observed inhibition of SARS-CoV-2, however, infection with attenuated, apathogenic influenza vaccine does not result in an aberrant immune response and enhanced disease severity. Taken together, the data suggest that the concept of twinfection is deleterious and mitigation steps should be instituted as part of a comprehensive public health response to the COVID-19 pandemic.

microbiology↗