Neuropharmacology

Group Head

• Dr. Richard Loiacono

Background

Our group is interested in investigating the role of neurotransmitters, receptor families, and enzyme systems, in neurological disorders such as Schizophrenia, Alzheimer’s Disease and Parkinson’s Disease, with a focus on neuroprotection and agents that halt the progression of the neurodegenerative processes associated with these diseases.

Current projects

Nicotinic Receptors, Dopaminergic and Serotonergic Neurotransmission and Schizophrenia

Ms Nicola Ingram (PhD Student)

Schizophrenia is a debilitating disorder that affects approximately 1% of the population. Studies show that schizophrenia seems to be associated with changes to nicotinic receptors within the brain. In schizophrenia there is a loss of nicotinic receptors as the disease progresses, and, further studies have shown a genetic mutation in nicotinic receptors in patients suffering schizophrenia with the presence of an aberrant type of nicotinic receptor found in these patients. A very high proportion of schizophrenic patients smoke and it has been suggested that this may be a form of self-medication. It has been suggested that tobacco smoking may interact with, and possibly improve, the effects of drugs (the antipsychotic drug family) that are normally used in schizophrenia. The aim of my project is to investigate whether nicotine interacts with antipsychotic drugs and how this might occur. We have shown that nicotine affects PPI, a measure of the ability to filter or “gate” sensory information which is deficient in schizophrenia, and that nicotine interacts with clozapine, but not haloperidol at this level. We have also shown that antipsychotics can regulate nicotinic receptors, despite having no direct action at these receptors. Antipsychotic drugs can also interact with nicotine treatment to regulate numbers of nicotinic receptors in a manner that is specific to the receptor subtype, region examined and drug investigated. Additionally, these drugs can also affect the genes of nicotinic receptors by altering levels of mRNA. This also appears to be specific to the nicotinic receptor subtype, drug and region examined. Currently, we are investigating the effects of nicotine and antipsychotic drugs on the signalling systems of neurons, by examining extracellular signal regulated kinase (ERK) a key protein in intracellular signalling.

Neuroprotective effects of ApoE and statins in Alzheimer’s Disease and neurodegeneration

Ms Fiona Kennon (PhD Student)

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder affecting 10% of people over the age of 65 and 50% of those over the age of 85. Clinically, AD is characterised by behavioural changes, progressive memory deficits, and reduced cognitive ability. These clinical symptoms are accompanied by neuronal degeneration and rapid abnormal physical changes in the brain. The pathological hallmarks of AD include neuritic plaques (primarily composed of fibrillar -amyloid) and neurofibrillary tangles (primarily composed of hyperphosphorylated tau), both of which are found throughout the brains of AD patients upon autopsy. Presently, there is not a single defined parameter responsible for the onset of AD, however potential risk factors include the presence of the e4 allele of the cholesterol transporting protein Apolipoprotein E (ApoE), mutations in AD related proteins which result in excess -amyloid production (APP, PS1, PS2), advanced age, diet, viruses, and hypercholesterolemia. Interestingly, factors which may delay the onset of AD include long term use of a particular class of cholesterol-lowering drugs known as the statins, and the absence of the e4 allele of ApoE. This project primarily focuses on the involvement of cholesterol and ApoE in the pathogenesis of AD and investigates the neuroprotective properties of a synthetic truncated ApoE peptide and two commonly prescribed statins in several in vivo models of neurodegeneration.

Inflammatory Processes and Oxidative Stress in Parkinson’s Disease

Mr Leigh Brown (PhD Student)
Ms Vanessa Brait (BMS Hons Student)

Parkinson’s disease (PD) is a prevalent, multifactorial disease characterized by the progressive death of dopamine neurons in areas of the brain controlling movement. The subsequent loss of the neurotransmitter dopamine results in severe motor abnormalities, and currently available drugs are inadequate for treating these symptoms and underlying pathology. Recent evidence suggests that neuroinflammation may contribute to the ongoing damage to dopamine neurons in PD, and animal models that mimic this component have been developed to investigate this process. This project uses several such models and examines the role of oxidative stress and the production of reactive oxygen species (ROS) as part of the process that leads to neuronal death and development of PD. Specifically, the project examines the role of several enzyme systems involved in the generation of ROS including NADPH oxidase (NOX) and its isoforms. Agents that block such enzymes and reduce ROS production may protect dopamine neurons in human PD. An additional aspect of this project investigates the antioxidant gene transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), and its potential for reducing oxidative stress. This study examines the levels and expression patterns of Nrf2 mRNA and selected target genes in mouse brain, and any alterations to this expression in mouse PD models. Agents that activate Nrf2 may be potential neuroprotective agents for a range of neurodegenerative diseases like PD.

Endocannabinoids in Neuroprotection

Ms Stephanie Robinson (PhD Student)

Cannabis is a commonly used drug of abuse around the world, and is now know to act upon a specific system with in the brain; the endocannabinoid system. The role of this system is complex and not well understood. Research into the system has provided some insight into the role in which it might serve in the brain, with one of the primary roles thought to be that of providing neuroprotection. This project is comprised of several parts. It firstly aims to examine the mRNA distribution of the various components of the endocannabinoid system in normal C57 mice, including the CB1 and CB2 receptors, as well as the enzymes that are responsible for the synthesis and degradation of the endogenous ligands (diacylglycerol lipase α and β, monacylglycerol lipase and fatty acid amide hydroxylase). It then subsequently aims to examine any regulatory changes in the components after the chronic administration of two drugs active in the endocannabinoid system; methanandamide and WIN,55212-2. Further, this project involves exploring the possible neuroprotective properties of endocannabinoids and related compounds in several models of neurodegeneration in mice; an excitotoxic model, a hypoxic-ischemic model and the middle cerebral artery occlusion model of stroke. The final part of this project involves using various techniques to examine the molecular mechanisms responsible for providing any neuroprotective properties. It is hoped that this project will increase our understanding of the role of both endogenous and exogenous cannabinoids in neurodegeneration and neuroprotection.

Group head

• Dr Richard Loiacono BSc (Hons) PhD

Group Members

• Ms Nicola Ingram (PhD Student)
• Ms Fiona Kennon (PhD Student)
• Mr Leigh Brown (PhD Student)
• Ms Stephanie Robinson (PhD Student)
• Ms Vanessa Brait (BMS Hons Student)

Recent key publications

1. Ryan, R. and Loiacono, R.E. (2000) Nicotinic receptor mRNA expression in rat thalamus – Relevance to human schizophrenia. Neuroreport 11 3693-8
2. Hemedah, M. Loiacono, R.E. Coupar, I.M and Mitchelson, F.J. (2001) Lack of evidence for histamine H3 receptor function in rat ileum and human colon. Naunyn Schmeideberg’s Arch Pharmacol 363 133-8
3. Ryan R.E and Loiacono, R.E. (2001). Upregulation in a7 nicotinic receptor subunit mRNA in rat - Role in addiction to nicotine. nicotinic receptors in a rat model of Alzheimer-type neurodegeneration. Neuroreport 12 569-72
4. Ryan, R.E., Ross, S., Drago, J. and Loiacono, R.E. (2001) Dose Related Neuroprotective Effects of Nicotine in 6-hydroxydopamine treated rats and a4 nicotinic receptor knockout mice. Brit J Pharmacol 132 1650-6
5. Henderson, D.J., Eberl, S., Thomson, S., Smith, A., Allan, R.D., Fulham, M.J., Loiacono, R.E. and Kassiou, M. (2004) 3-pyridyl ethers as SPECT radioligands for imaging nicotinic acetylcholine receptors. App Radiat Isot 60 669-76
6. Wickramaratna, J.C., Fry, B.G., Loiacono, R.E., Aguilar M.I., Alewood, P.F. and Hodgson W.C. (2004) Isolation and chracterisation at cholinergic nicotinc receptors of a neurotoxin from the venom of the Acanthophis sp. Seram death adder. Biochem Pharmacol 68, 383-94.
7. Ingram, N., Martin, S., Wang, J.H., van der Laan, S., Loiacono, R.E. and Van den Buusse, M (2005). Interaction of corticosterone and nicotine in regulation of prepulse inhibition in mice Neuropharmacol 48 80-92.