Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series.

WHAT IS KNOWN AND OBJECTIVE: Cannabidiol (CBD) is the main non-psychotropic component of the Cannabis sativa plant. REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during REM sleep associated with nightmares and active behaviour during dreaming. We have described the effects of CBD in RBD symptoms in patients with Parkinson's disease. CASES SUMMARY: Four patients treated with CBD had prompt and substantial reduction in the frequency of RBD-related events without side effects. WHAT IS NEW AND CONCLUSION: This case series indicates that CBD is able to control the symptoms of RBD.

Lack of tolerance for the anti-dyskinetic effects of 7-nitroindazole, a neuronal nitric oxide synthase inhibitor, in rats.

7-Nitroindazole (7-NI) inhibits neuronal nitric oxide synthase in vivo and reduces l-DOPA-induced dyskinesias in a rat model of parkinsonism. The aim of the present study was to determine if the anti-dyskinetic effect of 7-NI was subject to tolerance after repeated treatment and if this drug could interfere with the priming effect of l-DOPA. Adult male Wistar rats (200-250 g) with unilateral depletion of dopamine in the substantia nigra compacta were treated with l-DOPA (30 mg/kg) for 34 days. On the 1st day, 6 rats received ip saline and 6 received ip 7-NI (30 mg/kg) before l-DOPA. From the 2nd to the 26th day, all rats received l-DOPA daily and, from the 27th to the 34th day, they also received 7-NI before l-DOPA. Animals were evaluated before the drug and 1 h after l-DOPA using an abnormal involuntary movement scale and a stepping test. All rats had a similar initial motor deficit. 7-NI decreased abnormal involuntary movement induced by l-DOPA and the effect was maintained during the experiment before 7-NI, median (interquartile interval), day 26: 16.75 (15.88-17.00); day 28: 0.00 (0.00-9.63); day 29: 13.75 (2.25-15.50); day 30: 0.5 (0.00-6.25); day 31: 4.00 (0.00-7.13), and day 34: 0.5 (0.00-14.63), Friedman followed by Wilcoxon test,vs day 26, P < 0.05;. The response to l-DOPA alone was not modified by the use of 7-NI before the first administration of the drug (l-DOPA vs time interaction, F1,10 = 1.5, NS). The data suggest that tolerance to the anti-dyskinetic effects of a neuronal nitric oxide synthase inhibitor does not develop over a short-term period of repeated administration. These observations open a possible new therapeutic approach to motor complications of chronic l-DOPA therapy in patients with Parkinson's disease.

Lack of tolerance for the anti-dyskinetic effects of 7-nitroindazole, a neuronal nitric oxide synthase inhibitor, in rats

7-Nitroindazole (7-NI) inhibits neuronal nitric oxide synthase in vivo and reduces l-DOPA-induced dyskinesias in a rat model of parkinsonism. The aim of the present study was to determine if the anti-dyskinetic effect of 7-NI was subject to tolerance after repeated treatment and if this drug could interfere with the priming effect of l-DOPA. Adult male Wistar rats (200-250 g) with unilateral depletion of dopamine in the substantia nigra compacta were treated with l-DOPA (30 mg/kg) for 34 days. On the 1st day, 6 rats received ip saline and 6 received ip 7-NI (30 mg/kg) before l-DOPA. From the 2nd to the 26th day, all rats received l-DOPA daily and, from the 27th to the 34th day, they also received 7-NI before l-DOPA. Animals were evaluated before the drug and 1 h after l-DOPA using an abnormal involuntary movement scale and a stepping test. All rats had a similar initial motor deficit. 7-NI decreased abnormal involuntary movement induced by l-DOPA and the effect was maintained during the experiment before 7-NI, median (interquartile interval), day 26: 16.75 (15.88-17.00); day 28: 0.00 (0.00-9.63); day 29: 13.75 (2.25-15.50); day 30: 0.5 (0.00-6.25); day 31: 4.00 (0.00-7.13), and day 34: 0.5 (0.00-14.63), Friedman followed by Wilcoxon test,vs day 26, P < 0.05;. The response to l-DOPA alone was not modified by the use of 7-NI before the first administration of the drug (l-DOPA vs time interaction, F1,10 = 1.5, NS). The data suggest that tolerance to the anti-dyskinetic effects of a neuronal nitric oxide synthase inhibitor does not develop over a short-term period of repeated administration. These observations open a possible new therapeutic approach to motor complications of chronic l-DOPA therapy in patients with Parkinson’s disease.

Nitric oxide synthase inhibition attenuates L-DOPA-induced dyskinesias in a rodent model of Parkinson's disease.

Chronic L-DOPA pharmacotherapy in Parkinson's disease is often accompanied by the development of abnormal and excessive movements known as L-DOPA-induced dyskinesia. Rats with 6-hydroxydopamine lesion of dopaminergic neurons chronically treated with L-DOPA develop a rodent analog of this dyskinesia characterized by severe axial, limb, locomotor and orofacial abnormal involuntary movements. While the mechanisms by which these effects occur are not clear, they may involve the nitric oxide system. In the present study we investigate if nitric oxide synthase inhibitors can prevent dyskinesias induced by repeated administration of L-DOPA in rats with unilateral 6-hydroxydopamine lesion. Chronic L-DOPA (high fixed dose, 100 mg/kg; low escalating dose, 10-30 mg/kg) treatment induced progressive dyskinesia changes. Two nitric oxide synthase inhibitors, 7-nitroindazole (1-30 mg/kg) and NG-nitro-L-arginine (50 mg/kg), given 30 min before L-DOPA, attenuate dyskinesia. 7-Nitroindazolee also improved motor performance of these animals in the rota-rod test. These results suggest the possibility that nitric oxide synthase inhibitors may be useful to treat L-DOPA-induced dyskinesia.

Cannabidiol for the treatment of psychosis in Parkinson's disease.

The management of psychosis in Parkinson's disease (PD) has been considered a great challenge for clinicians and there is a need for new pharmacological intervention. Previously an antipsychotic and neuroprotective effect of Cannabidiol (CBD) has been suggested. Therefore, the aim of the present study was to directly evaluate for the first time, the efficacy, tolerability and safety of CBD on PD patients with psychotic symptoms. This was an open-label pilot study. Six consecutive outpatients (four men and two women) with the diagnosis of PD and who had psychosis for at least 3 months were selected for the study. All patients received CBD in flexible dose (started with an oral dose of 150 mg/day) for 4 weeks, in addition to their usual therapy. The psychotic symptoms evaluated by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire showed a significant decrease under CBD treatment. CBD did not worsen the motor function and decreased the total scores of the Unified Parkinson's Disease Rating Scale. No adverse effect was observed during the treatment. These preliminary data suggest that CBD may be effective, safe and well tolerated for the treatment of the psychosis in PD.

Role of nitric oxide on motor behavior.

The present review paper describes results indicating the influence of nitric oxide (NO) on motor control. Our last studies showed that systemic injections of low doses of inhibitors of NO synthase (NOS), the enzyme responsible for NO formation, induce anxiolytic effects in the elevated plus maze whereas higher doses decrease maze exploration. Also, NOS inhibitors decrease locomotion and rearing in an open field arena. These results may involve motor effects of this compounds, since inhibitors of NOS, NG-nitro-L-arginine (L-NOARG), N(G)-nitro-L-arginine methylester (L-NAME), N(G)-monomethyl-L-arginine (L-NMMA), and 7-Nitroindazole (7-NIO), induced catalepsy in mice. This effect was also found in rats after systemic, intracebroventricular or intrastriatal administration. Acute administration of L-NOARG has an additive cataleptic effect with haloperidol, a dopamine D2 antagonist. The catalepsy is also potentiated by WAY 100135 (5-HT1a receptor antagonist), ketanserin (5HT2a and alfal adrenergic receptor antagonist), and ritanserin (5-HT2a and 5HT2c receptor antagonist). Atropine sulfate and biperiden, antimuscarinic drugs, block L-NOARG-induced catalepsy in mice. L-NOARG subchronic administration in mice induces rapid tolerance (3 days) to its cataleptic effects. It also produces cross-tolerance to haloperidol-induced catalepsy. After subchronic L-NOARG treatment there is an increase in the density NADPH-d positive neurons in the dorsal part of nucleus caudate-putamen, nucleus accumbens, and tegmental pedunculupontinus nucleus. In contrast, this treatment decreases NADPH-d neuronal number in the substantia nigra compacta. Considering these results we suggest that (i) NO may modulate motor behavior, probably by interfering with dopaminergic, serotonergic, and cholinergic neurotransmission in the striatum; (ii) Subchronic NO synthesis inhibition induces plastic changes in NO-producing neurons in brain areas related to motor control and causes cross-tolerance to the cataleptic effect of haloperidol, raising the possibility that such treatments could decrease motor side effects associated with antipsychotic medications. Finally, recent studies using experimental Parkinson's disease models suggest an interaction between NO system and neurodegenerative processes in the nigrostriatal pathway. It provides evidence of a protective role of NO. Together, our results indicate that NO may be a key participant on physiological and pathophysiological processes in the nigrostriatal system.

Comparison of the mechanisms of latency shift in pattern reversal visual evoked potential induced by blurring and contrast reduction.

Reduction of visual acuity or of the contrast of the stimulus induces a prolongation of the pattern reversal visual evoked potential (PR-VEP) latencies, perhaps because these conditions cause deterioration of the visual capacity to recognize objects and may preferentially activate the slower central retina channel. The PR-VEP was obtained with a video stimulator and 3 kinds of stimuli: total video field, video with a central scotoma and a restricted central stimulus. The subjects were tested under conditions of normal (20/20) and reduced visual acuity (20/200) with 14' and 56' checks and 60% contrast, and under conditions of normal visual acuity (20/20) with 14' checks and with stimulus contrast of 60% and 25%. Blurring increased latencies and decreased amplitudes only with the 14' checks stimulus but no with 56' checks, and the amplitudes obtained with the central stimulus became greater than those obtained with a central scotoma. Reducing contrast increased only latency, and there was not difference between amplitudes obtained with a central stimulus or a central scotoma. We conclude that blurring small checks induces a preferential stimulation of receptors in the central retina, but the same effect was not observed when stimulus contrast was reduced.

Rural or urban living and Parkinson's disease.

Although the precise etiology of Parkinson's disease (PD) is as yet unknown, it appears that certain environmental factors are involved. Prior living in a rural area has been implicated as a possible risk factor for PD, particularly in the early onset type. We evaluated the role of previous living conditions in the clinical correlates and outcome characteristics of 118 PD patients. All of them were seen from January 1987 to October 1992. The Rural Group (RG) comprised 71 patients (60.2%) who had lived in the rural area for at least 10 years (mainly in early phase of life) and the Urban Group (UG) consisted of 47 patients (39.8%) who had lived their entire life in an urban environment. The average age at the beginning of the symptoms was 58.8 in the RG and 54.1 in the UG. The mixed form of the disease (tremor, rigidity and akinesia) was the most frequent in both groups. A minimum 6-month follow-up period was undertaken with 63 patients (average 20 months) and no difference in response to treatment or in progression of the illness was detected between the two groups. Our data show that the previous living environment does not appear to be a determining factor in either the clinical or outcome characteristics of PD.

[Abnormalities of pattern reversal evoked visual potential in patients with defined multiple sclerosis]. / Anormalidades do potencial evocado visual por padrão reverso em pacientes com esclerose múltipla definida.

The pattern reversal visual evoked potential with checks of 14' and 28' was retrospectivelly studied in 28 patients with definite multiple sclerosis. We observed abnormal responses in 27/28 (96.4%) patients, in 31/36 (86%) of symptomatic eyes, and in 16/20 (80%) of asymptomatic eyes. When we classified the abnormalities in each eye according to the findings obtained with each check, there was a correlation between the pattern of abnormalities and the severity of visual involvement. Occasionally there were isolated abnormalities of N75 or only in P100 obtained with 28' checks. In conclusion the methodology applied was very sensible in detecting abnormalities in visual pathway. We could classify the findings in each eye and correlate them with the severity of visual involvement. The findings showed uneven distribution of lesions in visual pathway, affecting preferentially the central vision afferents.

Mouse interferon receptors: a difference in their response to alpha and beta interferons.

The interferon receptors of C3H/10T1/2 mouse cells respond differently to alpha and beta interferons under certain conditions. If C3H/10T1/2 cells which have been maintained in logarithmic growth phase are exposed to trypsin or Pronase immediately before they are treated with mouse interferons, they evince an antiviral response to alpha interferon but not to beta interferon. In contrast, contact-inhibited C3H/10T1/2 cells, L-929 mouse cells or human HEL cells lost the ability to respond to both alpha and beta interferons after treatment with trypsin or Pronase. When L-929 cells are incubated at 37 degrees C following exposure to these proteolytic enzymes, they completely regain their ability to respond to mouse beta interferon within 2 h. These observations suggest that the receptors for alpha and beta interferons are different in their topographical distribution in C3H/10T1/2 cells.