ORCID Profile
0000-0002-4650-2220
Current Organisations
Monash University
,
Monash Institute of Pharmaceutical Sciences
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Elsevier BV
Date: 08-2009
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.PSYNEUEN.2019.05.004
Abstract: Angiotensin AT
Publisher: Frontiers Media SA
Date: 29-01-2021
DOI: 10.3389/FPHAR.2020.606656
Abstract: The M 1 and M 4 muscarinic acetylcholine receptors (mAChRs) are highly pursued drug targets for neurological diseases, in particular for Alzheimer’s disease and schizophrenia. Due to high sequence homology, selective targeting of any of the M 1 -M 5 mAChRs through the endogenous ligand binding site has been notoriously difficult to achieve. With the discovery of highly subtype selective mAChR positive allosteric modulators in the new millennium, selectivity through targeting an allosteric binding site has opened new avenues for drug discovery programs. However, some hurdles remain to be overcome for these promising new drug candidates to progress into the clinic. One challenge is the potential for on-target side effects, such as for the M 1 mAChR where over-activation of the receptor by orthosteric or allosteric ligands can be detrimental. Therefore, in addition to receptor subtype selectivity, a drug candidate may need to exhibit a biased signaling profile to avoid such on-target adverse effects. Indeed, recent studies in mice suggest that allosteric modulators for the M 1 mAChR that bias signaling toward specific pathways may be therapeutically important. This review brings together details on the signaling pathways activated by the M 1 and M 4 mAChRs, evidence of biased agonism at these receptors, and highlights pathways that may be important for developing new subtype selective allosteric ligands to achieve therapeutic benefit.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.XPHS.2021.11.003
Abstract: The expression of voltage-gated potassium Kv1.3 channels is increased in activated microglia, with non-selective blockade reported to attenuate microglial-mediated neuroinflammation. In this study, we evaluated the impact of a potent and selective peptidic blocker of Kv1.3 channels, HsTX1[R14A], on microglial-mediated neuroinflammation in vitro and in vivo. Treatment with both 0.1 and 1 µg/mL lipopolysaccharide (LPS) significantly (p < 0.05) increased Kv1.3 abundance on the surface of BV-2 microglia in association with increased levels of mRNA for tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The increased transcription of TNF-α and IL-6 was significantly attenuated (by 24.9 and 20.2%, respectively) by HsTX1[R14A] (100 nM). The concomitant increase in TNF-α and IL-6 release from BV-2 microglia was significantly attenuated by HsTX1[R14A] by 10.7 and 12.6%, respectively. In LPS-treated primary mouse microglia, the levels of TNF-α and nitric oxide were also attenuated by HsTX1[R14A] (26.1 and 20.4%, respectively). In an LPS-induced mouse model of neuroinflammation, both an immediate and delayed subcutaneous dose of HsTX1[R14A] (2 mg/kg) significantly reduced plasma and brain levels of the pro-inflammatory mediators TNF-α, IL-1β and IL-6, with no impact on the anti-inflammatory IL-10. These results demonstrate that HsTX1[R14A] is a promising therapeutic candidate for the treatment of diseases with a neuroinflammatory component.
Publisher: Wiley
Date: 2009
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.BBI.2018.03.007
Abstract: Epidemiological evidence suggests that people with bipolar disorder prescribed lithium exhibit a lower risk of Alzheimer's disease (AD) relative to those prescribed other mood-stabilizing medicines. Lithium chloride (LiCl) reduces brain β-amyloid (Aβ) levels, and the brain clearance of Aβ is reduced in AD. Therefore, the purpose of this study was to assess whether the cognitive benefits of LiCl are associated with enhanced brain clearance of exogenously-administered Aβ. The brain clearance of intracerebroventricularly (icv) administered
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.EURONEURO.2007.03.011
Abstract: The development of schizophrenia may include an early neurodevelopmental stress component which increases vulnerability to later stressful life events, in combination leading to overt disease. We investigated the effect of an early stress, in the form of maternal deprivation, combined with a later stress, simulated by chronic periadolescent corticosterone treatment, on behaviour in rats. Acute treatment with apomorphine caused disruption of prepulse inhibition (PPI) in controls and in rats that had undergone either maternal deprivation or corticosterone treatment, but was surprisingly absent in rats that had undergone the combined early and late stress. Amphetamine treatment significantly disrupted PPI in both non-deprived groups, but was absent in both maternally deprived groups. The serotonin-1A receptor agonist, 8-OH-DPAT, induced a significant disruption of PPI in all groups. Amphetamine-induced locomotor hyperactivity was similar in all groups. These results show an inhibitory interaction of early stress, caused by maternal deprivation, combined with 'adolescent' stress, simulated by corticosterone treatment, on dopaminergic regulation of PPI. The altered effects of apomorphine and hetamine could indicate differential changes in dopamine receptor signalling leading to functional desensitisation, or altered modulation of sensory gating in the nucleus accumbens by limbic structures such as the hippoc us.
Publisher: SAGE Publications
Date: 10-2020
Abstract: Although COVID-19 is predominantly a respiratory disease, it is known to affect multiple organ systems. In this article, we highlight the impact of SARS-CoV-2 (the coronavirus causing COVID-19) on the central nervous system as there is an urgent need to understand the longitudinal impacts of COVID-19 on brain function, behaviour and cognition. Furthermore, we address the possibility of intergenerational impacts of COVID-19 on the brain, potentially via both maternal and paternal routes. Evidence from preclinical models of earlier coronaviruses has shown direct viral infiltration across the blood–brain barrier and indirect secondary effects due to other organ pathology and inflammation. In the most severely ill patients with pneumonia requiring intensive care, there appears to be additional severe inflammatory response and associated thrombophilia with widespread organ damage, including the brain. Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy. Available reports suggest possible vertical transmission of SARS-CoV-2, although longitudinal cohort studies of such offspring are needed. The impact of paternal infection on the offspring and intergenerational effects should also be considered. Research targeted at mechanistic insights into all aspects of pathogenesis, including neurological, neuropsychiatric and haematological systems alongside pulmonary pathology, will be critical in informing future therapeutic approaches. With these future challenges in mind, we highlight the importance of national and international collaborative efforts to gather the required clinical and preclinical data to effectively address the possible long-term sequelae of this global pandemic, particularly with respect to the brain and mental health.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 14-09-2016
Abstract: Current antipsychotics are effective in treating the positive symptoms associated with schizophrenia, but they remain suboptimal in targeting cognitive dysfunction. Recent studies have suggested that positive allosteric modulation of the M
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1007/S00213-011-2609-5
Abstract: Vigilant scanning of the environment is a major risk assessment activity in many species. However, due to difficulties in its manual scoring, scanning has rarely been quantified in laboratory rodent studies. We developed a novel method for automated measurement of vigilant scanning in mice, based on simultaneous tracking of an animal's nose- and center-points. The studied scanning parameters included the frequency and duration of scans and scanning (nose-point) speed. The sensitivity of these parameters to anxiolytic diazepam (1-2 mg/kg) and anxiogenic FG-7142 (5 mg/kg) was evaluated upon exposure to the context (conditioning chamber) before and 24 h after footshock. Scanning behavior was observed in all C57BL/6, 129xC57BL/6, and DBA/2 mice, as recurrent stationary episodes accompanied by observatory head movements. These episodes respectively comprised 28 ± 1%, 29 ± 1%, and 24 ± 2% of preexposure time. Diazepam dose-dependently decreased the scanning frequency and duration, without affecting the scanning speed. Fear conditioning increased freezing and inhibited other behaviors upon reexposure, with scanning being only marginally affected and still comprising 17 ± 2%, 16 ± 2%, and 19 ± 1% of reexposure time, respectively. Consequently, scanning accounted for most (DBA/2) or virtually all (C57BL/6 and 129xC57BL/6) gross motor activities upon reexposure. FG-7142 mirrored the effects of conditioning, inducing behavioral inhibition with scanning being least affected. Two-point tracking is effective for studying vigilant scanning in mice. Using this approach, we show that scanning is a key risk assessment activity in both unconditioned and conditioned mice scanning is resistant to threat-induced behavioral inhibition and is highly sensitive to anxiolytic treatment.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2021
DOI: 10.1038/S41398-021-01662-7
Abstract: Between adolescence and adulthood, the brain critically undergoes maturation and refinement of synaptic and neural circuits that shape cognitive processing. Adolescence also represents a vulnerable period for the onset of symptoms in neurodevelopmental psychiatric disorders. Despite the wide use of rodent models to unravel neurobiological mechanisms underlying neurodevelopmental disorders, there is a surprising paucity of rigorous studies focusing on normal cognitive-developmental trajectories in such models. Here, we sought to behaviorally capture maturational changes in cognitive trajectories during adolescence and into adulthood in male and female mice using distinct behavioral paradigms. C57 BL/6J mice (4.5, 6, and 12 weeks of age) were assessed on three behavioral paradigms: drug-induced locomotor hyperactivity, prepulse inhibition, and a novel validated version of a visuospatial paired-associate learning touchscreen task. We show that the normal maturational trajectories of behavioral performance on these paradigms are dissociable. Responses in drug-induced locomotor hyperactivity and prepulse inhibition both displayed a ‘U-shaped’ developmental trajectory lower during mid-adolescence relative to early adolescence and adulthood. In contrast, visuospatial learning and memory, memory retention, and response times indicative of motivational processing progressively improved with age. Our study offers a framework to investigate how insults at different developmental stages might perturb normal trajectories in cognitive development. We provide a brain maturational approach to understand resilience factors of brain plasticity in the face of adversity and to examine pharmacological and non-pharmacological interventions directed at ameliorating or rescuing perturbed trajectories in neurodevelopmental and neuropsychiatric disorders.
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.NBD.2012.03.015
Abstract: Psychiatric illnesses, such as schizophrenia, are most likely caused by an interaction between genetic predisposition and environmental factors, including stress during development. The neurotrophin, brain-derived neurotrophic factor (BDNF) has been implicated in this illness as BDNF levels are decreased in the brain of patients with schizophrenia. The aim of the present study was to assess the combined effect of reduced BDNF levels and postnatal stress, simulated by chronic young-adult treatment with the stress hormone, corticosterone. From 6 weeks of age, female and male BDNF heterozygous mice and their wild-type controls were chronically treated with corticosterone in their drinking water for 3 weeks. At 11 weeks of age, male, but not female BDNF heterozygous mice treated with corticosterone exhibited a profound memory deficit in the Y-maze. There were no differences between the groups in baseline prepulse inhibition (PPI), a measure of sensorimotor gating, or its disruption by treatment with MK-801. However, an increase in startle caused by MK-801 treatment was absent in male, but not female BDNF heterozygous mice, irrespective of corticosterone treatment. Analysis of protein levels of the NMDA receptor subunits NR1, NR2A, NR2B and NR2C, showed a marked increase of NR2B levels in the dorsal hippoc us of male BDNF heterozygous mice treated with corticosterone. In the ventral hippoc us, significantly reduced levels of NR2A, NR2B and NR2C were observed in male BDNF heterozygous mice. The NMDA receptor effects in hippoc al sub-regions could be related to the spatial memory deficits and the loss of the effect of MK-801 on startle in these mice, respectively. No significant changes in NMDA receptor subunit levels were observed in any of the female groups. Similarly, no significant changes in levels of BDNF or its receptor, TrkB, were found other than the expected reduced levels of BDNF in heterozygous mice. In conclusion, the data show differential interactive effects of reduced levels of BDNF expression and corticosterone treatment on spatial memory and startle in male and female mice, accompanied by significant, but region-specific changes in NMDA receptor subunit levels in the dorsal and ventral hippoc us. These results could be important for our understanding of the interaction of neurodevelopmental stress and BDNF deficiency in cognitive and anxiety-related symptoms of psychiatric illnesses, such as schizophrenia.
Publisher: American Chemical Society (ACS)
Date: 14-12-2019
DOI: 10.1021/ACSCHEMNEURO.8B00613
Abstract: Targeting allosteric sites of the M
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.EJPHAR.2010.09.035
Abstract: Glutathione (GSH) is the primary antioxidant in the body and is present in high levels in the brain. Levels of GSH and other antioxidants are significantly altered in major psychiatric illnesses, such as schizophrenia. Recent clinical trials have demonstrated that chronic treatment with N-acetyl-l-cysteine (NAC), a GSH precursor, improved symptoms in in iduals with this illness. We previously showed in rats and mice that depletion of GSH by treatment with 2-cyclohexene-1-one (CHX) induced short-term spatial memory deficits in the Y-maze test. The aim of present study was to characterise the effect of NAC in this CHX-induced glutathione depletion model. Consistent with our previous studies, CHX treatment induced approximately 50% reduction of GSH levels in striatum, hippoc us and frontal cortex tissue. GSH depletion was significantly rescued by either 1.2 g/kg or 1.6 g/kg of NAC administration, with a full recovery observed in the frontal cortex after the high dose of NAC. CHX treatment also induced a disruption in short-term spatial recognition memory in Y-maze test, as measured by the duration of time spent in the novel arm. This disruption was reversed by treatment with 1.6 g/kg of NAC. In conclusion, this study suggests that rescue of depleted levels of GSH in the brain restores cognitive deficits, as measured by the Y-maze. These effects appear to be dose-dependent and region-specific. These results may be relevant to the understanding and management of the cognitive symptoms of schizophrenia and bipolar disorder.
Publisher: Elsevier BV
Date: 08-2009
Publisher: Society for Neuroscience
Date: 16-11-2016
DOI: 10.1523/JNEUROSCI.1583-16.2016
Abstract: Fatty acid-binding protein 5 (FABP5) at the blood–brain barrier contributes to the brain uptake of docosahexaenoic acid (DHA), a blood-derived polyunsaturated fatty acid essential for maintenance of cognitive function. Given the importance of DHA in cognition, the aim of this study was to investigate whether deletion of FABP5 results in cognitive dysfunction and whether this is associated with reduced brain endothelial cell uptake of exogenous DHA and subsequent attenuation in the brain levels of endogenous DHA. Cognitive function was assessed in male and female FABP5 +/+ and FABP5 −/− mice using a battery of memory paradigms. FABP5 −/− mice exhibited impaired working memory and short-term memory, and these cognitive deficits were associated with a 14.7 ± 5.7% reduction in endogenous brain DHA levels. The role of FABP5 in the blood–brain barrier transport of DHA was assessed by measuring 14 C-DHA uptake into brain endothelial cells and capillaries isolated from FABP5 +/+ and FABP5 −/− mice. In line with a crucial role of FABP5 in the brain uptake of DHA, 14 C-DHA uptake into brain endothelial cells and brain capillaries of FABP5 −/− mice was reduced by 48.4 ± 14.5% and 14.0 ± 4.2%, respectively, relative to those of FABP5 +/+ mice. These results strongly support the hypothesis that FABP5 is essential for maintaining brain endothelial cell uptake of DHA, and that cognitive deficits observed in FABP5 −/− mice are associated with reduced CNS access of DHA. SIGNIFICANCE STATEMENT Genetic deletion of fatty acid-binding protein 5 (FABP5) in mice reduces uptake of exogenous docosahexaenoic acid (DHA) into brain endothelial cells and brain capillaries and reduces brain parenchymal levels of endogenous DHA. Therefore, FABP5 in the brain endothelial cell is a crucial contributor to the brain levels of DHA. Critically, lowered brain DHA levels in FABP5 −/− mice occurred in tandem with cognitive deficits in a battery of memory paradigms. This study provides evidence of a critical role for FABP5 in the maintenance of cognitive function via regulating the brain uptake of DHA, and suggests that upregulation of FABP5 in neurodegenerative diseases, where brain DHA levels are possibly diminished (e.g., Alzheimer's disease), may provide a novel therapeutic approach for restoring cognitive function.
Publisher: IOP Publishing
Date: 11-04-2017
No related grants have been discovered for K.H. Christopher Choy.