The anti-depressant effects of a novel PDE4 inhibitor derived from resveratrol.

CONTEXT: Resveratrol has shown anti-stress and anti-depressant-like abilities involved in inhibiting phosphodiesterase-4 (PDE4) enzyme. However, its application is limited due to its low efficacy, bioavailability and selectivity. OBJECTIVE: This study synthesized a new resveratrol derivative RES003 and evaluated its PDE4 inhibitory and anti-depressant-like activities in vitro and in vivo, respectively. MATERIALS AND METHODS: PDEs inhibitory activities were evaluated by radioactive tracer method. Anti-depressant-like activities of novel resveratrol analogue (RES003) at doses of 2.5, 5.0 and 10 mg/kg was investigated by sugar water consumption and forced swimming tests using male ICR mice under chronic unpredictable stress procedure for 10 days. A total of 84 mice were randomly distributed into seven groups (n = 12). Drugs and vehicle were administered (intra-gastric or intra-peritoneal) once a day from the first to the last day. The molecular mechanisms were identified by western blot. RESULTS: RES003 showed more potent PDE4 inhibitory activity (half maximal inhibitory concentration (IC50), 0.87 µM) and better selectivity than resveratrol (IC50, 18.8 µM). RES003 could significantly increase the consumption of sugar water (p < 0.01) and immobility time (p < 0.01) compared to vehicle-treated stressed groups at doses of 5 and 10 mg/kg. Furthermore, RES003 could significantly increase the levels of cyclic adenosine monophosphate response element binding protein phosphorylation (10 mg/kg, p < 0.05) and brain-derived neurotrophic factor (BDNF) expression (5 and 10 mg/kg, p < 0.05 and 0.01) in mouse brain. DISCUSSION AND CONCLUSIONS: RES003 could ameliorate chronic stress induced depression-like behaviours through inhibition of PDE4 and activation of cAMP-triggered phosphorylation of cAMP response element binding protein/BDNF signalling pathway. Consequently, RES003 is a promising lead compound for the treatment of depression.

Spontaneous, Voluntary, and Affective Behaviours in Rat Models of Pathological Pain.

In pain patients affective and motivational reactions as well as impairment of daily life activities dominate the clinical picture. In contrast, many rodent pain models have been established on the basis of mechanical hypersensitivity testing. Up to today most rodent studies on pain still rely on reflexive withdrawal responses only. This discrepancy has likely contributed to the low predictive power of preclinical pain models for novel therapies. Here, we used a behavioural test array for rats to behaviourally evaluate five aetiologically distinct pain models consisting of inflammatory-, postsurgical-, cephalic-, neuropathic- and chemotherapy-induced pain. We assessed paralleling clinical expressions and comorbidities of chronic pain with an array of behavioural tests to assess anxiety, social interaction, distress, depression, and voluntary/spontaneous behaviours. Pharmacological treatment of the distinct pain conditions was performed with pathology-specific and clinically efficacious analgesics as gabapentin, sumatriptan, naproxen, and codeine. We found that rats differed in their manifestation of symptoms depending on the pain model and that pathology-specific analgesics also reduced the associated behavioural parameters. Based on all behavioural test performed, we screened for tests that can discriminate experimental groups on the basis of reflexive as well as non-sensory, affective parameters. Together, we propose a set of non-evoked behaviours with a comparable predictive power to mechanical threshold testing for each pain model.

Assessment of owner-directed aggressive behavioural tendencies of dogs in situations of possession and manipulation.

Excessive aggression is a common behaviour problem in dogs that can have various destructive effects on the affected people and the implicated dog. Aggressive behaviour directed towards the owner or other family members is one of the most frequently occurring aggressive phenotypes. Here, we examine the reliability of a short questionnaire assessing aggressive behaviours by two, contextually different behavioural tests: 'take away bone' and 'roll over'. Based on dogs' behaviour in the tests, we sorted dogs (N = 93) in two groups for each test, namely a less and a more disobedient/resistant group. The two principal components obtained in our questionnaire-'obedient' and 'aggressive towards owner'-showed significant differences between the behaviour groups. While dogs in the less disobedient/resistant groups had significantly higher 'obedient' and significantly lower 'aggressive towards owner' scores, dogs in the more disobedient/resistant groups had significantly higher 'aggressive towards owner' and significantly lower 'obedient' scores. Dogs' age, sex and neuter/spay status expressed their effect through interactions. Males, young dogs and intact dogs were less 'obedient' than older ones, while resistant spayed/neutered dogs were more aggressive towards the owner. The questionnaire used is a safe, easy to deploy and time-efficient tool to reliably assess certain owner-directed aggressive tendencies of family dogs.

Castration had no effect on decreased expression of the neural cell adhesion molecule in the prefrontal cortex of rats subjected to chronic mild stress.

The effect of chronic mild stress on protein levels of the neural cell adhesion molecule (NCAM) were evaluated in the prefrontal cortex and hippocampus of rat brain. Decreased NCAM protein expression in the prefrontal cortex was found in the rats subjected to stress, while the protein levels in sub-regions of hippocampus remained unchanged. The study also explored whether there was a testicular hormone influence on the behavioral response to stress and on the NCAM expression. We found chronic mild stress induced an anhedonia-like behavior in intact rats, but not in the castrated male rats. Furthermore, castration did not have influence on the stress induced reduction of NCAM expression in the prefrontal cortex. In conclusion, our findings indicate that NCAM mediated remodelling in the prefrontal cortex under chronic mild stress condition might be independent to the sex hormones during the adult period in male rat.