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New development in translational research in schizophrenia: towards therapy and prevention beyond dopamine antagonism

Interview with Prof. Kim Q. DO, recorded at ECNP Congress 2016, Vienna

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Prof. Do describes the interaction of oxidative stress with neuroinflammation and glutamate/NDMA receptor hypofunction. A translational approach is taken, involving both the clinical (patients) and preclinical (animal models) components: from symptoms in patients research goes to animal models for the underlying mechanism, then back to patients to identify biomarkers for early detection. It is possible to identify where genetic and environmental risks interact and lead to oxidative stress; this could have a critical impact on impairment of microcircuits. Oxidative stress can also impact on macrocircuits by affecting myelin.

There is an interaction between NDMA-receptor hypofunction and oxidative stress. NDMA-receptor hypofunction is connected to schizophrenia. There is a feed-forward loop in which NDMA-receptor hypofunction leads to oxidative stress, then bivalbumin intaneuron impairment, resulting in impairment of microcircuits. It is important to intervene early in vicious cycles like this. Research has paved the way for biomarker-guided treatment with antioxidant with no side effects.

Transcript

Q. Could you give a brief outline of your presentation, including an overview of the interaction of oxidative stress with neuroinflammation and glutamate/NMDA hypotension?

A. My presentation today concerns a translational approach in which we have both the clinical component and the preclinical components, and animal models where, coming from alterations in patients, we go to animal models for the mechanism and then go back to patients for identifying early biomarkers and also a new mechanism for early detection. Thanks to this approach, we can identify one core mechanism in which genetic risk and environmental risk interact during development, leading to oxidative stress.  This oxidative stress, which is in full interaction with NMDA receptor hypofunction, or redoxis regulation, or dopamine dysregulation or also neuroinflammation, would have a critical impact on impairment of microcircuits, specifically on parvalbumin internal roles. The parvalbumin internal roles is very critical for neurosynchronisation and cognitive function. This is the impact on microcircuits but this oxidative stress can also have an impact on macrocircuits through impairment in myelin and oligodendrocytes, which are the cells which make myelin.  That impairment of parvalbumin and the myelin could be at the basis of problems with connectivity and problems of neural synchronisation, which could be the basis of dimension – a dimension that we know from schizophrenia. Let me talk a little about this kind of interaction, as you have asked.  In animal models, we can show that oxidative stress –so  in animal models where we can make a knock-out of the desensitising enzyme of glutathione, which has been shown to be decreased in patients in both CSF and in the brain – we knock out the desensitising enzyme of glutathione.  We have a model where glutathione is decreased by 50 to 70 per cent and we see that, actually, the decrease of impairment in parvalbumin, which again is key for any cognitive function, thanks to their synchronisation, gamma-synchronisation, properties. What we have also found in these glutathione deficient models is that we can see that the insults, the environmental insults – only the early environmental insults, during the peri-pubertal period, have a deleterious effect on these parvalbumin internal roles. That persists until adulthood, while adult insults, adult trauma, has no effect on that parvalbumin internal role.  This has a tremendous consequence, which I will show a little about in terms of prevention. This is concerning interaction with redoxis regulation – so glutathione deficit and oxidative stress.  What we also see is this interaction between NMDA receptor hypofunction and oxidative stress.  NMDA receptor hypofunction has been known to play a very critical role in schizophrenia, as an antagonist linked to many symptoms in schizophrenia.  We can also show that there is a kind of feed-forward loop, a reciprocal feed-forward loop, in which NMDA receptor hypofunction leads to oxidative stress and then parvalbumin internal roles impairment.  Oxidative stress can also lead to NMDA receptor hypofunction through acting on the redoxite.  There is a feed-forward vicious cycle, which then leads to the impairment of micro-circuits. Concerning oxidative stress and neuroinflammation, these are quite recent unpublished results, where we can see that in our oxidative stress model, neuroinflammation happens already very early during development, and perhaps neuroinflammation has to be seen early, before the symptoms come.  Again, here, we have identified the mechanism in this interaction, tapping on matrix metalloproteinase activation and the shedding of receptor for ?advent critation product, and then, in turn, boosting the pro-inflammatory cytokines and micro activation which, in turn, leads to more free radicals and more oxidative stress.  Again, here, we have a feed-forward reciprocal loop, vicious cycle, that we need to intervene very, very early, thanks to the matrix metalloproteinase inhibitors.  This is the new mechanism that we have highlighted today: perhaps we can talk about the implications on the clinical side.

Q. What are the potential implications before clinical practice, in particular, for early intervention?

A. In this model, we see that the impairment, specifically of the parvalbumin internal roles, which are critical for cognition, can all be rescued by giving N-acetyl cysteine (NAC), which is an antioxidant, and glutathione precursor.  This has quite important implications for clinics because, as I have told you, we have a translation project and, after seeing that, this can be prevented by the application of NAC. We went on to make a proof of concept, a supplementation clinical trial, which was double-blind, randomised and placebo controlled, with NAC, in 140 patients.  This was together with the group from Melbourne and ?Michael Bear.   This was in chronic schizophrenia patients and we saw a net improvement of negative symptoms and also an improvement of mismatch negativity, which is an EEG component related to an NMDA receptor hypofunction and also improvement of gamma synchronisation.  These are promising results but now, as I have told you, we need prevention, and so we go now to an earlier stage of psychosis. We have just finished clinical trials with the add-on of NAC in 60 patients, with for us, ?AP result, so early psychosis patients.  This is the first time that I have given these results and actually we can see that NAC, in early psychosis patients, improves or increases the brain glutathione levels.  This means that there is drug target engagement, and also improved neurocognition, specifically the speed processing.  In terms of symptoms, globally, we do not see any change in symptoms but, if we now stratify the patients according to their peripheral oxidation status that we can measure in blood at baseline, the group of patients will have high oxidation status improved significantly in positive symptoms. This change also paralleled the change in the redox state in the blood.  That has paved the way for biomarker-guided treatment, with such an antioxidant which has really no effects, no side effects.  That could pave the way also in terms of new therapeutic targets, and specifically pave the way for prevention.

Q. What is your take-home message?

A. The take-home message is in two things.  In order to advance the field and also to improve the outcome, we know that psychosis evolves through various stages, from prodrome to chronic schizophrenia.  A delay in the treatment has a negative impact on the outcome and increases the relapse rate, and so we need to do early interventions, but to do early intervention we need biomarkers.  We also need to understand the mechanism, but we can only do that through a translational approach because for mechanism, we have to go to models, coming from alteration in patients and going to animal models for the mechanism, and then, don’t forget, going back to the patient.  This is the main message, a translational approach.  Secondly, we also need to intervene early with safe antioxidants, so really safe, or redox modulator – perhaps that opens the way to early intervention, to prevent.