Tramadol/paracetamol treatment attenuates the development of collagen antibody-induced arthritis and interferes with prednisolone treatment in mice.

The collagen antibody-induced arthritis (CAIA) model is highly effective in inducing arthritis, making it an attractive model for screening therapeutic compounds such as glucocorticoids (GCs). The severity of discomfort in this model makes it desirable to administer analgesics, but it is a prerequisite that these do not interfere with the model or tested therapeutics. In the present study, we studied the effect of 1 mg/mL tramadol and 3.5 mg/mL paracetamol (TP) on CAIA in male BALB/cAnNCrl mice and the possible interference of TP analgesia with the activity of the GC drug prednisolone (Pred). Our results showed that TP abolished the Pred-induced amelioration of CAIA, as well as several other Pred-induced effects, such as the reduction in thymus weight and the increase in insulin level. This most likely results from the effects of TP on the hepatic metabolism of this drug, since it strongly increased the Cyp3a11 expression in the liver. Altogether, we conclude that TP analgesia is not suitable for the CAIA model in male BALB/cAnNCrl mice, in particular when evaluating the effects of GCs such as Pred.

RandoMice, a novel, user-friendly randomization tool in animal research.

Careful design of experiments using living organisms (e.g. mice) is of critical importance from both an ethical and a scientific standpoint. Randomization should, whenever possible, be an integral part of such experimental design to reduce bias thereby increasing its reliability and reproducibility. To keep the sample size as low as possible, one might take randomization one step further by controlling for baseline variations in the dependent variable(s) and/or certain known covariates. To give an example, in animal experiments aimed to study atherosclerosis development, one would want to control for baseline characteristics such as plasma triglyceride and total cholesterol levels and body weight. This can be done by first defining blocks to create balance among groups in terms of group size and baseline characteristics, followed by random assignment of the blocks to the various control and intervention groups. In the current study we developed a novel, user-friendly tool that allows users to easily randomize animals into blocks and identify random block divisions that are well-balanced based on given baseline characteristics, making randomization time-efficient and easy-to-use. Here, we present the resulting software tool that we have named RandoMice.

Neuroprotective effects of riluzole in early phase Parkinson's disease on clinically relevant parameters in the marmoset MPTP model.

The present study evaluates neuroprotection in a marmoset MPTP (1-methyl-1,2,3,6-tetrahydropyridine) model representing early Parkinson's disease (PD). The anti-glutamatergic compound riluzole is used as a model compound for neuroprotection. The compound is one of the few protective compounds used in the clinic for a neurodegenerative disorder. Marmoset monkeys were randomized into three groups of six: 1) an MPTP group receiving a total MPTP dose of 7 mg/kg (4 injections over two weeks, s.c.) 2) a riluzole group receiving besides MPTP, a twice daily dose of riluzole (10 mg/kg, p.o.), starting one week before MPTP and continuing for one week after the final MPTP injection and 3) a control group receiving saline instead of MPTP and riluzole. The marmosets' Parkinsonian symptoms were scored daily and their activity level, hand-eye coordination, jumping behavior, axial turning and night sleep parameters were tested and recorded weekly. At three weeks following the last MPTP challenge, brains were dissected and dopamine levels in the striatum and the tyrosine hydroxylase (TH) expressing dopamine (DA) neurons in the substantia nigra (SN) were compared. MPTP affected all behavioral parameters and sleep architecture and induced a relatively mild (50%) decline of DA neurons in the substantia nigra (SN). Riluzole relieved the Parkinsonian signs, and improved the hand-eye coordination as well as turning ability. Moreover, riluzole prevented the impact of MPTP on sleep architecture and rapid eye movement behavioral disorder (RBD). Riluzole also increased the number of surviving DA neurons in MPTP-treated marmosets to 75%. However, riluzole did not prevent the MPTP-induced impairments on locomotor activity and jumping activity. In conclusion, reduction of excitotoxicity by riluzole appeared to be effective in reducing progressive neurodegeneration and relieved several clinically relevant PD symptoms in an animal model representing the early phase of PD.

REM sleep behavior disorder in the marmoset MPTP model of early Parkinson disease.

STUDY OBJECTIVES: Sleep problems are a common phenomenon in most neurological and psychiatric diseases. In Parkinson disease (PD), for instance, sleep problems may be the most common and burdensome non-motor symptoms in addition to the well-described classical motor symptoms. Since sleep disturbances generally become apparent in the disease before motor symptoms emerge, they may represent early diagnostic tools and a means to investigate early mechanisms in PD onset. The sleep disturbance, REM sleep behavior disorder (RBD), precedes PD in one-third of patients. We therefore investigated sleep changes in marmoset monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), the non-human primate model for idiopathic PD. DESIGN: Mild parkinsonism was induced in 5 marmoset monkeys (3M/2F) over a 2-week period of subchronic MPTP treatment. Electroencephalograms (EEGs) and electromyograms (EMGs) were recorded weekly. Motor activity and hand-eye coordination were also measured weekly, and any signs of parkinsonism were noted each day. Sleep parameters, motor activity, and performance data before and after MPTP treatment were compared between MPTP-treated marmosets and 4 control marmosets (1M/3F). RESULTS: MPTP increased the number of sleep epochs with high-amplitude EMG bouts during REM sleep relative to control animals (mean ± SEM percentage of REM 58.2 ± 9.3 vs. 29.6 ± 7.7; P < 0.05). Of all sleep parameters measured, RBD-like measures discriminated best between MPTP-treated and control animals. On the other hand, functional motor behavior, as measured by hand-eye coordination, was not affected by MPTP treatment (correct trials MPTP: 23.40 ± 3.56 vs. control: 36.13 ± 5.88 correct trials; P = 0.32). CONCLUSIONS: This REM sleep-specific change, in the absence of profound changes in wake motor behaviors, suggests that the MPTP marmoset model of PD could be used for further studies into the mechanisms and treatment of RBD and other sleep disorders in premotor symptom PD.

Two new test methods to quantify motor deficits in a marmoset model for Parkinson's disease.

The validity of the common marmoset (Callithrix jacchus) as a model for human disease depends on the development of parameters with clinical relevance. We tested the effect of treatment with MPTP in two newly developed non-invasive motor behavioral paradigms in the context of Parkinson's disease. The "Tower" was designed to quantify the marmoset's natural jumping behavior as a measure for akinesia, the "Hourglass" to test the marmoset's natural righting reflex as measure for rigidity, analogous to axial motor behavior in humans. MPTP treatment affected marmoset behavior in both testing paradigms. The marmoset's righting reflex in the Hourglass remained significantly impaired during the full 3-week period after the MPTP intoxication. In the Tower, the marmosets were not able to jump the largest distances one week after MPTP and showed a persistent reduction in activity during the 3-week period after the MPTP intoxication. Because not all aspects of motor behavior are similarly affected by MPTP, a complete behavioral sketch of parkinsonian marmosets should preferably include a range of motor behavior functions to create an overview of the full range of motor impairments. Both the Hourglass and Tower test provide important behavioral parameters in a clinically relevant multiple testing approach in motor disorder models.

Involvement of group II metabotropic glutamate receptors in stress-induced behavioural sensitization.

RATIONALE: A short session of repeated foot shocks in rats causes long-lasting sensitization of behavioural, hormonal and autonomic responses to novel stressful challenges. The behavioural sensitization can be reduced by anxiolytics and mimics aspects of stress-induced changes in patients with post-traumatic stress disorder. OBJECTIVES: The aim of this study was to test the efficacy of a group II metabotropic glutamate receptor (mGluR) agonist and assess altered brain mGluR receptor expression in shock-sensitized rats. MATERIALS AND METHODS: Male Wistar rats were exposed to a 15-min session with ten 6-s foot shocks (preshocked). One and 2 weeks later, rats were intraperitoneally injected with the group II metabotropic glutamate receptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) or vehicle, and 30 min later exposed to 5 min of 85 dB noise. For in situ hybridization with probes for mGluR1, mGluR2, mGluR3 and mGluR5, preshocked and control rats were killed under basal conditions 2 weeks after foot shocks and their brains cryosectioned. RESULTS: APDC had no clear effect in controls, but dose-dependently reduced high immobility and increased low locomotion and rearing seen in preshocked rats to the levels of controls. mGluR3 expression was increased in the basolateral nucleus of the amygdala, and mGluR2 expression was increased in the agranular insular cortex of preshocked rats compared to controls. CONCLUSIONS: Shock-induced behavioural sensitization in rats is reduced by acute treatment with a group II metabotropic glutamate receptor agonist. This effect may depend on the increased expression of amygdala mGluR3, which could be hypothesized as an endogenous mechanism to counteract stress-induced neuronal sensitization.