The Antiparkinsonian and Antidyskinetic Mechanisms of Mucuna pruriens in the MPTP-Treated Nonhuman Primate.

Chronic treatment with levodopa (LD) in Parkinson's disease (PD) can cause drug induced dyskinesias. Mucuna pruriens endocarp powder (MPEP) contains several compounds including natural LD and has been reported to not cause drug-induced dyskinesias. We evaluated the effects of Mucuna pruriens to determine if its underlying mechanistic actions are exclusively due to LD. We first compared MPEP with and without carbidopa (CD), and LD+CD in hemiparkinsonian (HP) monkeys. Each treatment ameliorated parkinsonism. We then compared the neuronal firing properties of the substantia nigra reticulata (SNR) and subthalamic nucleus (STN) in HP monkeys with MPEP+CD and LD+CD to evaluate basal ganglia circuitry alterations. Both treatments decreased SNR firing rate compared to HP state. However, LD+CD treatments significantly increased SNR bursting firing patterns that were not seen with MPEP+CD treatments. No significant changes were seen in STN firing properties. We then evaluated the effects of a water extract of MPEP. Oral MPWE ameliorated parkinsonism without causing drug-induced dyskinesias. The distinctive neurophysiological findings in the basal ganglia and the ability to ameliorate parkinsonism without causing dyskinesias strongly suggest that Mucuna pruriens acts through a novel mechanism that is different from that of LD.

The effect of striatal dopaminergic grafts on the neuronal activity in the substantia nigra pars reticulata and subthalamic nucleus in hemiparkinsonian rats.

The electrophysiological correlates of parkinsonism in the basal ganglia have been well studied in patients with Parkinson's disease and animal models. Separately, striatal dopaminergic cell transplantation has shown promise in ameliorating parkinsonian motor symptoms. However, the effect of dopaminergic grafts on basal ganglia electrophysiology has not thoroughly been investigated. In this study, we transplanted murine foetal ventral mesencephalic cells into rats rendered hemiparkinsonian by 6-hydroxydopamine injection. Three months after transplantation, extracellular and local field potential recordings were taken under urethane anaesthesia from the substantia nigra pars reticulata and subthalamic nucleus along with cortical electroencephalograms and were compared to recordings from normal and hemiparkinsonian controls. Recordings from cortical slow-wave activity and global activation states were analysed separately. Rats with histologically confirmed xenografts showed behavioural improvement measured by counting apomorphine-induced rotations and with the extended body axis test. Firing rates in both nuclei were not significantly different between control and grafted groups. However, burst firing patterns in both nuclei in the slow-wave activity state were significantly reduced (P < 0.05) in rats with large surviving grafts, compared to hemiparkinsonian controls. The neuronal firing entropies and oscillations in both nuclei were restored to normal levels in the large-graft group. Electroencephalogram spike-triggered averages also showed normalization in the slow-wave activity state (P < 0.05). These results suggest that local continuous dopaminergic stimulation exerts a normalizing effect on the downstream parkinsonian basal ganglia firing patterns. This novel finding is relevant to future preclinical and clinical investigations of cell transplantation and the development of next-generation therapies for Parkinson's disease that ameliorate pathophysiological neural activity and provide optimal recovery of function.

Satiety-responsive neurons in the medial orbitofrontal cortex of the macaque.

Feeding-related gustatory, olfactory, and visual activation of the orbitofrontal cortex (OFC) decreases following satiety. Previous neurophysiological studies have concentrated on the caudolateral OFC (clOFC). We describe satiety-induced modulation of 23 gustatory, 5 water, and 15 control neurons in the medial OFC (mOFC), where gustatory neurons represent a much larger percentage of the population. For 15 of the 23 gustatory neurons (65%), every significant taste response evoked during pre-satiety testing decreased following satiety (X=70%). Responses evoked by the ineffective taste stimuli during pre-satiety testing were unchanged following satiety. The graded response decrements of the mOFC gustatory neurons stand in marked contrast to the clOFC responses, which are almost completely suppressed by satiety. Two other novel findings are reported here. First, all significant pre-satiety taste responses of four gustatory neurons increased following satiety (X=51%). Second, post-satiety emergent taste responses were observed in 7 of 15 neurons (47%) classified as non-responsive during pre-satiety testing. The presence of increased responsiveness and emergent gustatory neurons in the mOFC suggests that meal termination may require active processes as well as the passive loss of hedonic value.