fbpx New mechanisms underlying mood disorders | Progress In Mind

New mechanisms underlying mood disorders

Disturbed glutamatergic function may be involved in the aetiology of depression. In the search for new antidepressant targets, basic scientists are using animal models to investigate signaling events downstream from the NMDA receptor. The JNK pathway and neuronal nitric oxide synthases are of particular interest.

Might JNK inhibitors have therapeutic potential?

The JUN amino terminal kinases (JNK) are activated by cellular stress and play a part in apoptosis. Genetic susceptibility to psychiatric disorders in humans is associated with disruption of JNK pathway signalling, and this stress kinase appears to regulate anxiety and depression-like behaviours in mice.  JNK1 plays an active role in the developing brain. It is also expressed in adulthood, but we know less about its role. Even so, might JNK inhibitors have therapeutic potential?

This is the question being asked by Eleanor Coffey, University of Turku, Finland.

JNK1 knockout animals display less anxiety than wild type animals. Dr Coffey and colleagues were not able to show that acute inhibition of JNK1 altered anxiety behaviour. But chronic treatment with an inhibitor decreased “anxious” behaviour in adult mice and increased neurogenesis in the hippocampus. In patients, hippocampal neurogenesis is required for the action of antidepressants; so this phenomenon may be relevant to treatment. In Dr Coffey’s model, if mitosis is blocked by administration of Ara-C, the anxiolytic effect of the inhibitor is reduced.

Inhibition of JNK in the neurogenic niche also alleviates “depressed” behaviour modelled by the forced swim test. Inhibition of nuclear JNK in the newborn granule cells of the dentate gyrus is sufficient to induce a non-anxious phenotype and alleviate depressive behaviour.

Ketamine without the adverse events?

Might agents that act downstream of the NMDA receptor give us the antidepressant efficacy of ketamine without that agent’s adverse effects? Modifiers of NMDA signalling are putative antidepressants, Andrew Harkin (Trinity College Dublin, Ireland) told the meeting. For that reason, he has been investigating nitric oxide (NO) synthase inhibitors. Such inhibitors appear to have antidepressant-like effects in the forced swim paradigm.

Dr Harkin has been using the Wistar Kyoto rat, an inbred strain with a marked depressive phenotype and a demonstrable reduction in hippocampal volume. The imidazole NO synthase inhibitor TRIM has an antidepressant effect in this model and also appears able to reverse the reduction in neural complexity induced by NMDA.

Test compounds in rodent models have a delayed but sustained antidepressant effect. The delay suggests a novel mechanism involving neuroplasticity. Such agents may have problematic off-target effects on the vasculature, so we need new compounds which are selective for NO synthase on the NMDA receptor. But the NO synthase/NMDA interface remains a potentially interesting target.

Life as a lonely rat

Early neglect is a risk factor for depression in humans. And Kevin Fone, of the Queen’s Medical Centre, University of Nottingham, UK, has been using a model in which rats are reared from weaning in social isolation. This has adverse effects on the animals, which are sociable by nature, and leads to a range of abnormalities including hyperactivity in novel environments and deficits in memory and associative learning.

Current anxiolytic agents can reverse the “anxious” behaviour of animals placed in an unfamiliar cage, and Dr Fone was able to show that a 5-HT6 antagonist could reverse the cognitive impairments seen in animals reared in isolation.. 

Also relevant is the fact that rats reared in social isolation show reduced volume of the medial prefrontal cortex similar to that seen in people with depression.

Such findings suggest that this rodent model of neurodevelopment might be useful in screening new compounds for therapeutic potential.

You are leaving Progress in Mind
Le informazioni contenute nel nuovo sito prescelto possono non essere conformi al D.Ivo 219/06 che regola la pubblicità dei medicinali per uso umano e le opinioni espresse non riflettono necessariamente le posizioni dell’azienda, non sono da essa avvallate.
Accesso riservato a Operatori Sanitari
Per accedere si prega di registrarsi o, in caso sia già stato fatto, di autenticarsi
L’accesso a Progress in Mind Italia è consentito unicamente agli Operatori Sanitari (medici e farmacisti). I contenuti di questo sito sono prodotti da un team di Operatori Sanitari il cui obiettivo è presentare le ultime novità in ambito psichiatrico e neurologico, attraverso interviste, registrazioni audio/video di seminari con opinion leader, report e sintesi di congressi sia internazionali che nazionali. Per poter accedere al sito è quindi necessario registrarsi e fornire alcuni dati così da poter verificare che l‘utente sia un Operatore Sanitario.
Per accedere alla pagina si prega di registrarsi o, in caso sia già stato fatto, di autenticarsi. La pagina per la quale sta richiedendo l'accesso ospita materiale formativo comunque attinente all'impiego di medicinali prodotti o commercializzati da Lundbeck. Con riferimento al Decreto Legislativo n.219 del 24 aprile 2006 e s.m.i., art. 119, art. 121 comma 1 e art. 124 commi 4 e 8, Lundbeck limita l'accesso ai contenuti presenti nella pagina PIM Academy a medici specialisti e farmacisti ospedalieri.
Please confirm your email
We have just sent you an email, with a confirmation link.
Before you can gain full access - you need to confirm your email.
The information on this site is exclusively intented for health care professionals.
All the information included in the Website is related to products of the local market and, therefore, directed to health professionals legally authorized to prescribe or dispense medications with professional practice. The technical information of the drugs is provided merely informative, being the responsibility of the professionals authorized to prescribe drugs and decide, in each concrete case, the most appropriate treatment to the needs of the patient.
Register for access to Progress in Mind in your country