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Professor Bruno Frenguelli

Professor of Neuroscience

Email: B.G.Frenguelli@warwick.ac.uk 

Phone: 024 761 50591

Office: IBRB1.26 

Frenguelli webpage


Research Clusters

Neuroscience


Warwick Centres and GRPs

Behaviour, Brain & Society


Vacancies and Opportunities

For PhD and postdoctoral opportunities, and interest in potential collaborations, please contact me at the above email address.


Research Interests

The lab’s focus is on how a class of molecules known as the purines affect the brain and nervous system, and how they can be used to both diagnose brain disorders and as novel treatments. The most important purines are ATP – the energy source used by all cells, including brain cells, and adenosine – the “A” in ATP. When the brain faces high energy demand, eg during epileptic seizures, or a disruption in the supply of blood, such as during stroke, ATP is consumed, liberating adenosine, which switches off energy-demanding process. In doing so adenosine tries to preserve ATP levels and to protect the brain during these conditions. Importantly, the production of adenosine during these events in the brain results in the appearance of adenosine and its breakdown products in the blood stream. While this may be used to diagnose stroke and other brain injuries, this loss from the brain of these molecules denies the brain of the ability to re-make ATP from them. Part of the research effort in the lab is to try and restore the brain’s ability to make ATP through the provision of simple, safe and cheap ingredients already in use in humans. Another part of the effort is to work with a company, ZP, developing sensors to detect purine-based biomarkers for brain injury. An additional aspect of the lab’s purine research involves a novel molecule we have discovered that, like adenosine, has painkilling properties, but is devoid of the effects on the cardiovascular system and respiration. These side-effects have prevented development of such adenosine-based molecules as painkillers. We hope that this compound and its derivatives, which we have patented and licensed to a drug-testing company, will be of value in the development of new, non-opioid analgesics.

Research: Technical Summary

The purines ATP and adenosine play fundamental roles in biology; the former as the universal energy currency, an extracellular signalling molecule, and as the primary reservoir of adenosine, while the latter has powerful neuroprotective and anticonvulsant actions in the brain following its release during ATP-depleting conditions such as epileptic seizures, stroke and traumatic brain injury. Under these conditions adenosine inhibits glutamate release and hyperpolarises neurons to reduce both the impact of potentially neurotoxic glutamatergic signalling on neurons, and energy-intensive postsynaptic spiking, respectively. These properties of adenosine thus directly protect brain tissue and reduce the likelihood, intensity and duration of epileptic seizures, as well as other injury-related and damaging neurological phenomena such as cortical spreading depolarisation. While the appearance of adenosine and its metabolites in blood during these conditions can be used as a biomarker for brain injury, a topic we are pursuing in animal models of brain injury, this efflux into the blood deprives the brain of the substrates necessary for the production of ATP. In the brain, the primary route for the synthesis of ATP is via the purine salvage pathway, which converts adenine and hypoxanthine to AMP for subsequent production of ATP. We have found that the provision of adenine and ribose can elevate ATP levels in brain tissue, results in the greater production of adenosine with demonstrable effects on glutamatergic transmission in physiological and pathological conditions, and alone or in combination with a xanthine oxidase inhibitor to reduce breakdown of hypoxanthine, reduces brain injury and accelerates recovery in an animal model of stroke. We are now pursuing this approach in an a range of brain injury models.

Allied to its role as a neuroprotectant and anticonvulsant is adenosine’s action as an analgesic. However, profound cardiovascular effects (bradycardia, hypotension) and respiratory depression have dogged attempts to harness analgesia via the primary inhibitory adenosine receptor – the A1R. We have discovered an A1R agonist, BnOCPA, which is a powerful analgesic, but devoid of cardiorespiratory effects. This is likely due to its unprecedented ability to activate only one subtype of the Gαo/i subunits that A1Rs couple to (Gob), which is not found in the heart. This molecule provides a novel lead compound for A1R-based analgesics, and as a prototype for not just G-protein biased agonists, but G-protein selective agonists.

A research image

Publications

For a full list of publications, see WRAP

Biography

  • 2007 – Professor of Neuroscience, School of Life Sciences, University of Warwick
  • 1996 – 2007, Lecturer, Senior Lecturer and Caledonian Research Foundation Fellow, Department of Pharmacology & Neuroscience University of Dundee
  • 1993-1996, Wellcome Trust International Travelling Fellowship Cold Spring Harbor Laboratory, NY, USA and University of Bristol
  • 1993 PhD Neuropharmacology University of Birmingham
  • 1989 BSc Physiology University of Glasgow