Wednesday, 19 August 2015

Phosphodiesterase inhibition can make brainy mice

McGirr A, Lipina TV, Mun HS, Georgiou J, Al-Amri AH, Ng E, Zhai D, Elliott C, Cameron RT, Mullins JG, Liu F, Baillie GS, Clapcote SJ, Roder JC. Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition. Neuropsychopharmacology. 2015 Aug 14. doi: 10.1038/npp.2015.240. [Epub ahead of print]
Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358Cmice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 h, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signalling by PDE4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory.

So having painted a scene where 4PE4 inhibitors may have unwanted consequences, now we have the "super smart mouse" coming from inhibition of a PDE4, namely PDE4B. This is responsible for distributing such hormones as adrenalin in the organism, but is also allegedly connected to such pathologies as schizophrenia or manic-depressive illness. 

PDE4B is believed to be the PDE4 subtype involved in the anti-psychotic effects of PDE4 inhibitors such as rolipram

PDE4B-inhibited “brainy” mice usually learned faster, had a better memory and were able to solve more complex tasks than normal mice. The mice were able to recognize other mice they saw the day before and were quicker at finding and remembering things.Additionally, they tended to be less anxious and fearful as they preferred to spend time in open brightly lit places in contrast to normal mice that usually choose dark secluded spaces, to avoid being eaten by predators and they were less frightened by cat wee. 

Ibudilast is widely used in Japan to treat ischemic stroke and bronchial asthma. (The sten is last meaning anti-asthma drug) Ibudilast preferentially inhibits PDE3A, PDE4, PDE10 and PDE11 with lesser inhibition of a number of other families. It potently inhibits purified human PDE4A, 4B, 4C and 4D. 

So will Ibudilast increase ones cognitive capacity and thus slow down the degenerative element of MS, by improving cognitive reserve and making one less anxious? Is this the secret behind an effect on atrophy as it is known that other PDE4 inhibitors can effect memory. As with any treatment, the benefits are a balance between positive and negative effects. It depends where the balance lies to determine the benefit. 

The only way is to know is to test it.

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