Biology subjects

Powell, W. H.

Publications and source records attributed to Powell, W. H..

3 recordsLinked to original sources

bioRxiv2025

NLX-112 is anti-inflammatory, upregulates GDNF and is neuroprotective against MPTP-induced nigrostriatal dopaminergic degeneration in mice

NLX-112 is a potent and selective 5-HT1A agonist that has successfully completed phase 2A clinical trial for treatment of L-DOPA-induced dyskinesia in Parkinsons disease (PD). We investigated the neuroprotective activity of NLX-112 in a mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Four groups of mice received either saline (1ml/kg) daily for 15 days, MPTP (21.4 mg/kg for 5 days, preceded and followed by 5 days saline, NLX-112 (1mg/kg/day for 15 days) or combined MPTP + NLX-112. Two weeks following cessation of treatments, NLX-112-treated mice showed increased locomotor activity and reduced anxiety-like behaviour in an open-field test, consistent with sustained effects of 5-HT1A receptor activation. MPTP-treated male mice showed a significant reduction of dopaminergic (i.e., tyrosine hydroxylase immunoreactive; TH-ir) neurones in the substantia nigra (SN) and the striatum by 40 and 55%, respectively. NLX-112 treatment elicited a significant protection against MPTP-induced loss of TH-ir neurones and nerve terminals. MPTP also a markedly increased the levels of GFAP-ir astrocytes and Iba1-ir microglia in the SN, and co-expression of glial-derived neurotrophic factor (GDNF) in the GFAP-ir astrocytes in both the SN and the striatum. However, in MPTP treated mice, NLX-112, markedly reversed microglial expression in the SN, and upregulated GFAP/GDNF co-localisation in both the striatum and the SN. Overall, the present study demonstrates a robust neuroprotective effect of NLX-112 in a mouse model of PD by preventing microgliosis, upregulating GDNF and favouring sustained pro-locomotor activity.

pharmacology and toxicology↗

bioRxiv2021

Dioxin Disrupts Thyroid Hormone and Glucocorticoid Induction of klf9, a Master Regulator of Frog Metamorphosis

Frog metamorphosis, the development of an air-breathing froglet from an aquatic tadpole, is controlled by thyroid hormone (TH) and glucocorticoids (GC). Metamorphosis is susceptible to disruption by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AHR) agonist. Kruppel-Like Factor 9 (klf9), an immediate early gene in the endocrine-controlled cascade of expression changes governing metamorphosis, can be synergistically induced by both hormones. This process is mediated by an upstream enhancer cluster, the klf9 synergy module (KSM). klf9 is also an AHR target. We measured klf9 mRNA following exposures to triiodothyronine (T3), corticosterone (CORT), and TCDD in the Xenopus laevis cell line XLK-WG. klf9 was induced 6-fold by 50 nM T3, 4-fold by 100 nM CORT, and 3-fold by 175 nM TCDD. Co- treatments of CORT and TCDD or T3 and TCDD induced klf9 7- and 11-fold, respectively, while treatment with all 3 agents induced a 15-fold increase. Transactivation assays examined enhancers from the Xenopus tropicalis klf9 upstream region. KSM-containing segments mediated a strong T3 response and a larger T3/CORT response, while induction by TCDD was mediated by a region [~]1 kb farther upstream containing 5 AHR response elements (AHREs). This region also supported a CORT response in the absence of readily-identifiable glucocorticoid responsive elements, suggesting mediation by protein-protein interactions. A functional AHRE cluster is positionally conserved in the human genome, and klf9 was induced by TCDD and TH in HepG2 cells. These results indicate that AHR binding to upstream AHREs represents an early key event in TCDDs disruption of endocrine-regulated klf9 expression and metamorphosis.

pharmacology and toxicology↗

bioRxiv2019

An Aryl Hydrocarbon Receptor from the Caecilian Gymnopis multiplicata Suggests Low Dioxin Affinity in the Ancestor of All Three Amphibian Orders

The aryl hydrocarbon receptor (AHR) plays pleiotropic roles in the development and physiology of vertebrates in conjunction with xenobiotic and endogenous ligands. It is best known for mediating the toxic effects of dioxin-like pollutants such as 2,3,7,8-tetracholordibenzo-p-dioxin (TCDD). While most vertebrates possess at least one AHR that binds TCDD tightly, amphibian AHRs bind TCDD with very low affinity. Previous analyses of AHRs from Xenopus laevis (a frog; order Anura) and Ambystoma mexicanum (a salamander; order Urodela) identified three amino acid residues in the ligand-binding domain (LBD) that underlie low-affinity binding. In X. laevis AHR1{beta}, these are A354, A370, and N325. Here we extend the analysis of amphibian AHRs to the caecilian Gymnopis multiplicata, representing the remaining extant amphibian order, Apoda. G. multiplicata AHR groups with the monophyletic vertebrate AHR/AHR1 clade. The LBD includes all three signature residues of low TCDD affinity, and a structural homology model suggests that its architecture closely resembles those of other amphibians. In transactivation assays, the EC50 for reporter gene induction by TCDD was 17.17 nM, comparable to X. laevis AhR1{beta} (26.23 nM) and Ambystoma AHR (34.09 nM) and dramatically higher than mouse AhR (0.13 nM), a trend generally reflected in direct measures of TCDD binding. These shared properties distinguish amphibian AHRs from the high-affinity proteins typical of both more ancient vertebrate groups (teleost fish) and those that appeared more recently (tetrapods). We suggest that AHRs with low TCDD affinity represent a basal characteristic that evolved in a common ancestor of all three extant amphibian groups.\n\nResearch HighlightsO_LIA caecilian aryl hydrocarbon receptor exhibits low dioxin binding and sensitivity.\nC_LIO_LIThe proteins ligand-binding domain resembles frog and salamander AHRs in structure and function.\nC_LIO_LIAHR with low dioxin affinity likely evolved in a common ancestor of all three extant amphibian groups.\nC_LI\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC=\"FIGDIR/small/750653v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (61K):\norg.highwire.dtl.DTLVardef@1a8b05eorg.highwire.dtl.DTLVardef@1d308e4org.highwire.dtl.DTLVardef@1eceb1dorg.highwire.dtl.DTLVardef@13fe8fd_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗