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Development of in-vitro neural systems for the identification of agents with toxicological and pharmacological potential

Objective

To utilise the in vitro systems developed in BAP to clarify the mechanisms of action of compounds particularly analogues of endogenous neuroactive aminoacids with pharmacological and toxicological properties involved with brain cell synaptic functioning, proliferation and differentiation, in order to evaluate their potential as anticonvulsants; neuroprotective agents in excitotoxin-mediated neurodegenerative disease e.g. ischaemia and epilepsy; anti-gliosis agents and anticancer drugs; and their effects as causative agents in the processes of cytotoxicity, epilepogenicity and other convulsive states.
These investigations show that neural cell culture systems have important uses in identifying and screening compounds for toxic and beneficial properties. These methods are strengthened by emphasis on the elucidation of mechanisms of action. Competitive polymeracse chain reaction (PCR) technology has improved the sensitivity of the assay for low level fos expression. Studies on (hexachlorocyclohexane (HCH)) (lindane (delta HCH)) and diazepam (DZ) showed similar effects on the Na release test at similar concentrations suggesting a relationship with their known central nervous system (CNS) depressant activity.
Inhibition of butylbicyclophosphothionate [(355) TBPS] binding by convulsant polychlorocycloalkanes (PCCAs) correlates with their lethal dose (LD 50) values.
This neurotechnological proposal provides a multi-disciplinary approach with input from biochemists, pharmacologists, molecular biologists, immunologists and toxicologists to develop and validate in-vitro neuronal and non-neuronal cell systems for use in screening and testing compounds in order to evaluate (1) their potential for use as anticonvulsants; neuroprotective agents in excitotoxin-mediated neurodegenerative disease e.g. ischaemia, epilepsy; anti-gliosis agents and anti-cancer drugs; and (2) their deleterious effect as causative agents in the processes of cytotoxicity, terato-genicity and epilepogenicity and other convulsive states. It builds on the expertise generated by the BAP contractors and the ELWW on 'In-vitro screening in Neurotoxicology and pharmacology using neural primary cultures and cell lines'. The cell systems will include human and rodent brain cell lines (neuroblastoma and glioma) rodent primary cultures (neurons and astrocytes) and the multicellular brain slice system. End- points to be evaluated include receptor mediated cytotoxicity; anti-proliferative index; differentiation gene markers and inhibition of synaptic function including neurotransmitter release, receptor occupancy, receptor-effector coupling and downstream signalling events. Systems will be evaluated for reproducibility, in-vitro/in-vivo correlations and activity predictions based on computer-assisted molecular structural modelling.

Coordinator

THE PROVOST, FELLOWS AND SCHOLARS OF THE COLLEGE OF THE HOLY AND UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN HEREINAFTER TRINITY COLLEGE DUBLIN
Address
College Green
4 Dublin
Ireland

Participants (4)

Bibra International
United Kingdom
Address
Woodmansterne Road
SM5 4DS Carshalton
Consejo Superior de Investigaciones Científicas
Spain
Address
18-26,Jorde Girona Salgado
08034 Barcelona
Danmarks Farmaceutiske Højskole
Denmark
Address
Universitetsparken
2100 København Ø
University of St Andrews
United Kingdom
Address
North Street
KY16 9AL St Andrews