YOSHITOMI RESEARCH INSTITUTE OF NEUROSCIENCE IN GLASGOW
- Evolving improved drug therapies to treat schizophrenia 
YRING Directors
Professor Judy Pratt
Professor Brian Morris
Management Team
Prof. Trevor W. Stone
Dr. C.M.R. Turner
Dr M. Livingston
Dr P Shelbourne
Dr R. Hunter
Professor Gavin Reynolds
Links
IBLS
University of Glasgow
YRING represents a research collaboration between Mitsubishi Pharma Corporation (MPC; one of Japan?s leading pharmaceutical companies - formerly Yoshitomi Pharmaceutical Industries Ltd.), the University of Strathclyde and the University of Glasgow. YRING was established in 1997 with the assistance of the Scottish Biomedical Foundation, who acted to facilitate the investment between the two Universities and the Company.
Research within the Institute is directed by Professor Judith Pratt, BSc, PhD of the University of Strathclyde and Professor Brian Morris, BA PhD of the University of Glasgow. The collaboration brings together the expertise of neuroscientists, pharmacologists, geneticists and molecular biologists from the two Universities, clinicians from Gartnavel Royal Hospital and the Southern General Hospital and MPC scientists. Some 20 staff are involved in the research programme which aims to increase understanding of the neurobiological processes underlying psychosis and to discover and evaluate new drug targets for the treatment of schizophrenia.
YRING is located in custom designed laboratories and offices located in the West Medical Building at the University of Glasgow. In 2002, Mitsubishi Pharma Corporation funded a new, custom-built state of the art YRING Behavioural Neuroscience Unit in the Department of Physiology and Pharmacology at the University of Strathclyde and funded an expansion of the YRING facilities at the University of Glasgow.
Schizophrenia:
Schizophrenia is a severe form of mental illness that affects 1% of the population. The devastating symptoms of the disease result in life-long problems for the sufferers and their carers. Current drugs are effective against some of the symptoms (such as hallucinations and delusions) but are much less effective against other symptoms (such as social withdrawal, self-neglect and cognitive deficits). A further limitation is their tendency to cause unpleasant side-effects. (http://www.schizophrenia.co.uk)
Achievements:
During the first 5 years of the programme YRING developed an entirely new model of schizophrenia and identified a group of completely novel targets which are being exploited to develop a new generation of improved drugs to treat schizophrenia. Furthermore YRING has gained insight into the molecular mechanisms involved in schizophrenia with the identification of novel psychosis-related genes. Other studies provided new information on the mechanism of action of existing antipsychotic drugs.
The Strathclyde Institute of Drug Research, (SIDR), and the Dept of Chemistry based at the University of Strathclyde were involved in the identification of compounds that hit the novel target using their high throughput screening facilities and synthetic chemistry expertise. Using a library of natural products of enormous structural diversity, they searched for compounds with the desired characteristics for further drug development. The team at the Dept of Chemistry, lead by Professor Suckling and Professor Murphy, exploited the natural product information and translated this into novel chemical entities. This aspect of the research is now being developed further at MPC.
The success of the first phase of the programme has led to MPC funding further research in YRING from October 2002. This second phase is a NeuroPsychogenomics programme which aims to identify and characterise novel psychosis related genes . Professor Morris and Professor Pratt continue to direct the Institute. They are assisted by a multidisciplinary advisory team comprising Prof T.Stone, Dr C.M.R.Turner, Dr P Shelbourne(GU), Dr R.Hunter (Gartnavel Royal Hospital), Dr.M.Livingston (Southern General Hospital), Professor G Reynolds (University of Sheffield) and Dr. S.Hammond (SBF).
Research Activities
Some examples of the wide-ranging research activities at YRING are shown.
Development of a new model of schizophrenia
One of the key pathological features of schizophrenia is decreased metabolic activity in the prefrontal cortex (hypofrontality). This hypofrontality has been linked to the cognitive deficits of the disease. YRING have developed a new model, based upon phencyclidine. When chronically abused, phencyclidine can produce symptoms indistinguishable from those of schizophrenia. Using a chronic intermittent phencyclidine (PCP) treatment regime, YRING have demonstrated that PCP produces a hypofrontality and deficits in GABAergic neurone activity that mirror the deficits seen in schizophrenia. Moreover, deficits in executive function akin to those observed in schizophrenia accompany these neurochemical deficits. This model is the first model to be developed to mirror such deficits and as such should give valuable insight into the abnormal functioning that develops in schizophrenia.
Chronic PCP-induced hypofrontality
Chronic intermittent PCP treatment (b) produces reductions in local cerebral glucose use in the prefrontal cortex (PrL) compared to controls (a). Neither clozapine (c) or haloperidol (d) reverse these deficits, although clozapine reverses PCP-induced deficits in markers of GABAergic neurone activity
Image reproduced from (Cochran et al 2003; Neuropsychopharmacology 28, 265-275
Gene Expression profiling in psychotic tissue
YRING has also led the way in attempts to identify and characterise previously unknown genes involved in schizophrenia and its treatment. YRING is employing gene microarrays on which over 20,000 known and unknown genes can be monitored simultaneously. When tissue extracts are applied to these gene arrays, the intensity of each individual spot provides a measure of how strongly that particular gene is expressed in the tissue. Hence if a disease process causes a change in the level of expression of even a single gene out of the thousands on the array, this can be rapidly detected by monitoring the spot intensities. This approach has been exploited to identify previously unknown genes that may be involved in the development and treatment of schizophrenia.
Hybridisation of a gene after chronic PCP administration. Each gene is represented by 16 oligonucleotides
(a probe set)
Entire GeneChip of 8791 oligonucleotide probe sets after hybridisation with
RNA isolated from PCP treated rat brain tissue
YRING NeuroPsychogenomics programme (2002-date)
One of the fundamental principles of YRING is the close integration of clinical psychiatry with laboratory-based neuroscience. The current phase of the research is focused on the identification and characterisation of genes that lead to the development of schizophrenia. The research programme employs sophisticated molecular biology, cellular, brain imaging and behavioural techniques.
Several schizophrenia-related genes have been identified from the YRING chronic PCP model and these are being characterised further in the new programme. Transgenic mice are being analysed for the role of the genes in psychosis both neurochemically and by behavioural phenotyping to assess the role of the particular gene in tests predictive of the positive and negative symptoms of schizophrenia as well as specific aspects of cognition. This is integrated with a clinical programme whereby DNA samples from patients are assessed for polymorphisms of the identified genes.
Advances in technology now allow a more comprehensive genomic analysis of samples and this can now be conducted in precisely defined cell types. We are therefore exploiting these new technologies in the current programme.
Overall, the results of these functional genomic studies will provide new insights into the identification of genes that are important in the development of schizophrenia as well as providing new information on the role of such genes in fundamental neurobiological processes. This should provide the basis for the development of novel drugs with increased efficacy and tolerability to treat this debilitating disease.
Recent Publications
1) Cochran SM, Steward, L. Kennedy, M. McKerchar,C. Pratt, J.A. and Morris, B.J. (2003).
Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs Neuropsychopharmacology 28, vol 2,
2) Cochran, S.M. McKerchar, C.E.; Morris, B.J. and Pratt, J.A (2002).
Induction of differential patterns of local cerebral glucose metabolism and immediate early genes by acute clozapine and haloperidol. Neuropharmacology 43, 394-407
3) Cochran, S.M., Fujimura M, Morris BJ and Pratt JA (2002)
Acute and delayed effects of phencyclidine upon mRNA levels of markers of glutamatergic and GABAergic neurotransmitter function in the rat brain. Synapse 46, 206-214
4) Reid, L., Egerton, A., Morris, BJ and Pratt, JA. (2003)
Acute PCP administration produces an attention set shifting deficit and reduced neural activity in the medial frontal cortex of the rat. Soc Neurosci. 940.11
Patents:
1) British Patent Application 0007880.8 entitled ?Schizophrenia Related Genes? filed March 2000
2) PCT International Patent Application (PCT/GB01/01486) entitled ?Schizophrenia Related Genes? filed April 2001
3) Novel compounds for treating schizophrenia 1. Filed March 03
4) Novel compounds for treating schizophrenia 2. Filed March 03
5) A novel therapeutic target concept for schizophrenia. Filed March 03