Raymond A.P. Vanwersch

Exploring the neuroprotective effects of modafinil in a marmoset Parkinson model with immunohistochemistry, magnetic resonance imaging and spectroscopy.

Neuroprotective therapeutics stop or slow down the degeneration process in animal models of Parkinsons disease (PD). Neuronal survival in PD animal models is often measured by immunohistochemistry. However, dynamic changes in the pathology of the brain cannot be explored with this technique. Application of proton magnetic resonance (MR) imaging (MRI) and spectroscopy (MRS) can cover this lacuna as these techniques are non-invasive and can be repeated over time in the same animal. Therefore, the sensitivity of both techniques to measure changes in PD-pathology was explored in an experiment studying the neuroprotective effects of the vigilance enhancer modafinil in a marmoset PD model. Eleven marmoset monkeys were treated with the neurotoxin 1-methyl-1,2,3,6-tetrahydropyridine (MPTP). Six of these 11 animals, simultaneously, received a daily oral dose of modafinil (100 mg/kg) and five received vehicle for 27 days. MR experiments were performed at baseline and 1 and 3.5 weeks after the MPTP intoxication period after which brains were analyzed with immunohistochemistry. Tyrosine hydroxylase immunoreactive (TH-IR) staining of dopamine neurons of the substantia nigra pars compacta confirmed that modafinil was able to partially prevent the MPTP-induced neuronal damage. In MRS, N-acetylaspartate (NAA)/phosphocreatine (tCR) ratios confirmed the protective effect indicating that this is a sensitive measure to detect neuroprotection in the MPTP marmoset model. Furthermore, the number of TH-IR positive neurons and the NAA/tCR ratio were significantly correlated to behavioral observations indicating that the changes measured in the brain are also reflected in the behavior and vice versa.

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.

Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects

The vigilance-enhancing agent modafinil has neuroprotective properties: it prevents striatal ischemic injury, nigrostriatal pathway deterioration after partial transsection and intoxication with 1-methyl-1,2,3,6-tetrahydropyridine. The present study determines the protective effects of modafinil in the marmoset 1-methyl-1,2,3,6-tetrahydropyridine Parkinson model on behavior and on monoamine levels. Twelve marmoset monkeys were treated with a total dose of 6 mg/kg 1-methyl-1,2,3,6-tetrahydropyridine. Simultaneously, six animals received a daily oral dose of modafinil (100 mg/kg) and six animals received vehicle for 27 days. Behavior was observed daily and the locomotor activity, hand–eye coordination, small fast movements, anxiety-related behavior and startle response of the animals were tested twice a week for 3 weeks. Modafinil largely prevented the 1-methyl-1,2,3,6-tetrahydropyridine-induced change in observed behavior, locomotor activity, hand–eye coordination and small fast movements, whereas the vehicle could not prevent the devastating effects of 1-methyl-1,2,3,6-tetrahydropyridine. Dopamine levels in the striatum of the vehicle+1-methyl-1,2,3,6-tetrahydropyridine-treated animals were reduced to 5% of control levels, whereas the dopamine levels of the modafinil+1-methyl-1,2,3,6-tetrahydropyridine-treated animals were reduced to 41% of control levels. The present data suggest that modafinil prevents decrease of movement-related behavior and dopamine levels after 1-methyl-1,2,3,6-tetrahydropyridine intoxication and can be an efficaceous pharmacological intervention in the treatment of Parkinsons disease.

Therapeutic effects of Δ9-THC and modafinil in a marmoset Parkinson model

Current therapies for Parkinsons disease (PD) like l-dopa and dopamine (DA) agonists have declined efficacy after long term use. Therefore, research towards supplementary or alternative medication is needed. The implementation in PD can be expedited by application of compounds already used in the clinic. In this study the therapeutic effects of the psychoactive compounds Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and modafinil were tested in the 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-marmoset model for PD. The anti-parkinson effects of Delta(9)-THC (4 mg/kg) and modafinil (100 mg/kg) in parkinsonian marmosets were assessed with two behavioral rating scales covering parkinsonian symptoms and involuntary movements and two test systems assessing the locomotor activity and hand-eye coordination. Delta(9)-THC improved activity and hand-eye coordination, but induced compound-related side-effects. Modafinil improved activity and observed parkinsonian symptoms but not hand-eye coordination. It can be concluded that both compounds have therapeutic values and could supplement existing therapies for PD.

Neurofeedback training on sensorimotor rhythmin marmoset monkeys

Neurofeedback research in a model closely related to humans is recommended to rule out placebo effects and unspecific factors bridging the gap between nonvalidated empirical and standardized controlled research. In this article, telemetric sensorimotor rhythm (SMR; 11–14 Hz) feedback training in the marmoset monkey is applied to examine the monkeys capability to voluntary control their brain activity. Four monkeys, provided with two epidural bioelectric electrodes above the sensorimotor cortex, were trained with positive reinforcement on SMR measured by online analyses of 1.28 s electroencephalogram epochs in 30-min sessions. These monkeys learned within five sessions to increase their &agr; activity. The first evidence of nonhuman primates having an operant control over the SMR is provided, an initial step for a much-needed scientific basis to neurofeedback.

On the development of behavioral tolerance to organophosphates III: behavioral aspects.

As part of a study on the mechanisms underlying behavioral tolerance to cholinesterase-inhibiting organophosphates (OPs) the present investigation was focussed on behavioral procedures affecting the development of tolerance. The effects of chronic administration of the OPs DFP (600 micrograms/kg SC) and soman (60 micrograms/kg SC) were compared in rats. These doses do not cause detectable effects upon close observation of the animals. As was found before, behavioral tolerance developed following DFP, but not following soman. Repeated behavioral testing affected the development of tolerance. Cross-tolerance between these two inhibitors was not found. Surprisingly, when DFP was administered 48 hr after soman, all animals were observationally normal, and when soman was given 48 hr after DFP the majority of the animals died. This indicates that the sequence in which these inhibitors were administered was of major importance. It is concluded that practice-related and/or state-dependent factors are important for the development of behavioral tolerance and that one should be careful in making generalizing statements about tolerance to cholinesterase-inhibiting OPs.

Stress adversely affects efficacy of physostigmine–scopolamine pretreatment against soman in guinea pigs

During military operations, soldiers may be exposed to mixtures of chemicals and to physical, emotional and psychological stress factors, which all may influence efficacy of any treatment, including the nerve agent pretreatment regimen. The purpose of this study was therefore to investigate the influence of chronic intermittent, variable, unpredictable and uncontrollable stress conditions on the side effects and therapeutic efficacy of the combination of physostigmine (0.025 mg/kg/h) and scopolamine (0.018 mg/kg/h) as a pretreatment against 2 x LD50 soman intoxication in guinea pigs. Stress during pretreatment led to an increase of motor activity and an increase of power in the EEG delta2 frequency band. After chronic stress, exposure of pretreated animals to 2 x LD50 soman resulted in more severe intoxication symptoms, a more persistent effect on the startle response, and considerable more severe and persistent effects on the EEG power-spectrum, indicating irreversible brain damage.

Sensorimotor rhythm neurofeedback as adjunct therapy for Parkinson's disease

Neurofeedback may enhance compensatory brain mechanisms. EEG‐based sensorimotor rhythm neurofeedback training was suggested to be beneficial in Parkinsons disease. In a placebo‐controlled study in parkinsonian nonhuman primates we here show that sensorimotor rhythm neurofeedback training reduces MPTP‐induced parkinsonian symptoms and both ON and OFF scores during classical L‐DOPA treatment. Our findings encourage further development of sensorimotor rhythm neurofeedback training as adjunct therapy for Parkinsons disease which might help reduce L‐DOPA‐induced side effects.

EFFICACY OF PRETREATMENT AND TREATMENT AGAINST SOMAN INTOXICATION

The efficacy against lethality and post-intoxication incapacitation after 2x LD50 soman of different subacute pretreatment scenarios of 12 days was tested with or without post-intoxication therapy in guinea pigs. These pretreatment regimes were 1) the currently used pyridostigmine (PYR, 0.04 mg/kg/hr), 2) the combination of physostigmine (PHY, 0.025 mg/kg/hr) with the muscarinic receptor antagonist scopolamine (SCO, 0.018 mg/kg/hr), and 3) the combination of PHY with the anti-Parkinson drug procyclidine (PC, 3 mg/kg, sc). The post-intoxication therapy consisted of HI-6 (21.4 mg/kg, im), atropine sulphate (AS, 0.085 mg/kg, im), and diazepam (DZP, 0.21 mg/kg, im). Behavioral and observational read-out systems were used to elucidate theseverity of soman induced incapacitation.

Erratum to “Exploring the neuroprotective effects of modafinil in a marmoset Parkinson model with immunohistochemistry, magnetic resonance imaging and spectroscopy” [Brain Res. 1189 (2008) 219–228]

S.A.M. van Vliet⁎, E.L.A. Blezer, M.J. Jongsma, R.A.P. Vanwersch, B. Olivier, I.H.C.H.M. Philippens Department of Diagnosis and Therapy, TNO Defence, Security and Safety, Rijswijk, The Netherlands Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands Department of Psychopharmacology, Utrecht Institute of Pharmaceutical Sciences and Rudolf Magnus Institute of Neurosciences, Utrecht University, Utrecht, The Netherlands Department of Psychiatry, Yale University, school of Medicine, New Haven, CT, USA