Kala Venkiteswaran

A Water Extract of Mucuna pruriens Provides Long-Term Amelioration of Parkinsonism with Reduced Risk for Dyskinesias

Dopaminergic anti-parkinsonian medications, such as levodopa (LD) cause drug-induced dyskinesias (DID) in majority of patients with Parkinsons disease (PD). Mucuna pruriens, a legume extensively used in Ayurveda to treat PD, is reputed to provide anti-parkinsonian benefits without inducing DID. We compared the behavioral effects of chronic parenteral administration of a water extract of M. pruriens seed powder (MPE) alone without any additives, MPE combined with the peripheral dopa-decarboxylase inhibitor (DDCI) benserazide (MPE+BZ), LD+BZ and LD alone without BZ in the hemiparkinsonian rat model of PD. A battery of behavioral tests assessed by blinded investigators served as outcome measures in these randomized trials. In experiment 1, animals that received LD+BZ or MPE+BZ at high (6mg/kg) and medium (4mg/kg) equivalent doses demonstrated significant alleviation of parkinsonism, but, developed severe dose-dependent DID. LD+BZ at low doses (2mg/kg) did not provide significant alleviation of parkinsonism. In contrast, MPE+BZ at an equivalent low dose significantly ameliorated parkinsonism. In experiment 2, MPE without any additives (12mg/kg and 20mg/kg LD equivalent dose) alleviated parkinsonism with significantly less DID compared to LD+BZ or MPE+BZ. In experiment 3, MPE without additives administered chronically provided long-term anti-parkinsonian benefits without causing DID. In experiment 4, MPE alone provided significantly more behavioral benefit when compared to the equivalent dose of synthetic LD alone without BZ. In experiment 5, MPE alone reduced the severity of DID in animals initially primed with LD+BZ. These findings suggest that M. pruriens contains water-soluble ingredients that either have an intrinsic DDCI-like activity or mitigate the need for an add-on DDCI to ameliorate parkinsonism. These unique long-term anti-parkinsonian effects of a parenterally administered water extract of M. pruriens seed powder may provide a platform for future drug discoveries and novel treatment strategies in PD.

The immunological challenges of cell transplantation for the treatment of Parkinson's disease

Dopaminergic cell transplantation is an experimental therapy for Parkinsons disease (PD). It has many potential theoretical advantages over current treatment strategies such as providing continuous local dopaminergic replenishment, eliminating motor fluctuations and medication-induced dyskinesias, slowing down disease progression or even reversing disease pathology in the host. Recent studies also show that dopaminergic cell transplants provide long-term neuromodulation in the basal ganglia that simulates the combined effects of oral dopaminergic therapy and surgical therapies like deep brain stimulation, the contemporary therapeutic approach to advanced PD. However, dopaminergic cell transplantation in PD as not been optimized and current experimental techniques have many drawbacks. In published experiments to date of attempted dopaminergic grafting in PD, the major challenges are unacceptable graft-induced dyskinesias or failure of such grafts to exceed the benefits afforded by sham surgery. A deleterious host immune response to the transplant has been implicated as a major putative cause for these adverse outcomes. This article focuses on recent advances in understanding the immunology of the transplantation in PD and possible methods to overcome adverse events such that we could translate cell replacement strategies into viable clinical treatments in the future.

MRI evaluation of asymmetry of nigrostriatal damage in the early stage of early-onset Parkinson's disease.

INTRODUCTION The motor symptoms and signs of early-onset idiopathic Parkinsons disease (PD) in Hoehn and Yahr (H&Y) stage-1 are generally unilateral. We hypothesized that there would be detectable differences in the quantitative MRI parameters in these PD patients between the hemispheres contralateral to the clinically symptomatic and non-symptomatic body side. METHODS We tested this hypothesis by comparing transverse relaxation rates and diffusion tensor imaging (DTI) parameters in the substantia nigra and putamen between the two hemispheres contralateral to the symptomatic and non-symptomatic side in H&Y stage-1 PD patients who had onset of symptoms between ages of 40-59 years. RESULTS There were quantifiable hemispheric asymmetries in transverse relaxation rates in the substantia nigra, as well as fractional anisotropy and mean diffusivity in the putamen in early PD, which correlated with the unilaterality of motor symptoms as evaluated using the motor portion of the Unified Parkinsons Disease Rating Scale. CONCLUSION Transverse relaxation mapping and DTI demonstrated significant differences between the symptomatic and non-symptomatic hemispheres at the early stage of early-onset PD. These findings support the hypothesis of asymmetric neurodegeneration in the bilateral nigrostriatal pathways in the early stage of the disease.

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

Chronic treatment with levodopa (LD) in Parkinsons 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 Parkinsons 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 Parkinsons disease that ameliorate pathophysiological neural activity and provide optimal recovery of function.

Anatomically discrete functional effects of adenoviral clostridial light chain gene-based synaptic inhibition in the midbrain

The gene for the Light Chain fragment of Tetanus Toxin (LC) induces synaptic inhibition by preventing the release of synaptic vesicles. The present experiment applied this approach within the rat midbrain in order to demonstrate that LC gene expression can achieve functionally and anatomically discrete effects within a sensitive brain structure. The deep layers of the superior colliculus/deep mesencephalic nucleus (dSC/DpMe) that are located in the rostral midbrain has been implicated in fear-induced increase of the acoustic startle reflex (fear potentiated startle) but exists in close proximity to neural structures important for a variety of critical functions. The dSC/DpMe of adult rats was injected bilaterally with adenoviral vectors for LC, green fluorescent protein, or vehicle. Synaptobrevin was depleted in brain regions of adenoviral LC expression. LC gene expression in the dSC/DpMe inhibited the increase in startle amplitude seen with the control viral infection, and blocked context-dependent potentiation of startle induced by fear conditioning. Although LC gene expression reduced the absolute amount of cue-specific fear potentiated startle, it did not decrease percent potentiated startle to a cue, nor did it reduce fear-induced contextual freezing, nonspecific locomotor activity, or general health, indicating that its effects were functionally and anatomically specific. Thus, vector-driven LC expression inhibits the function of deep brain nuclei without altering the function of surrounding structures supporting its application to therapeutic neuromodulation.

Polysomnographic Features of Sleep Disturbances and REM Sleep Behavior Disorder in the Unilateral 6-OHDA Lesioned Hemiparkinsonian Rat

Sleep pattern disruption, specifically REM sleep behavior disorder (RBD), is a major nonmotor cause of disability in PD. Understanding the pathophysiology of these sleep pattern disturbances is critical to find effective treatments. 24-hour polysomnography (PSG), the gold standard for sleep studies, has never been used to test sleep dysfunction in the standard 6-OHDA lesioned hemiparkinsonian (HP) rat PD model. In this study, we recorded 24-hour PSG from normal and HP rats. Recordings were scored into wake, rapid eye movement (REM), and non-REM (NREM). We then examined EEG to identify REM periods and EMG to check muscle activity during REM. Normal rats showed higher wakefulness (70–80%) during the dark phase and lower wakefulness (20%) during the light phase. HP rats showed 30–50% sleep in both phases, less modulation and synchronization to the light schedule (P < 0.0001), and more long run lengths of wakefulness (P < 0.05). HP rats also had more REM epochs with muscle activity than control rats (P < 0.05). Our findings that the sleep architecture in the HP rat resembles that of PD patients demonstrate the value of this model in studying the pathophysiological basis of PD sleep disturbances and preclinical therapeutics for PD related sleep disorders including RBD.

Transfer entropy between cortical and basal ganglia electrophysiology

Linear measures such as cross-correlation, coherence, and directed transfer functions have previously been applied to investigate the functional connectivity between brain regions. However, such methods do not account for nonlinear interactions between the signals. Separately, dopaminergic cell transplants have been shown to provide symptomatic amelioration and partial electrophysiological normalization of aberrant basal ganglia firing patterns in Parkinsons Disease. However, the precise extent and mechanisms of basal ganglia electrophysiological normalization have remained unclear. In this experiment we computed the transfer entropy between electroencephalograms (EEGs) and basal ganglia local field potentials (LFPs) from urethane-anesthetized rats, in order to investigate both linear and nonlinear interactions. We used the 6-hydroxy-dopamine lesioned medial forebrain bundle hemiparkinsonian (HP) rat model, and recorded from the substantia nigra and subthalamic nucleus of normal rats, HP rats, and HP rats with murine fetal ventral mesencephalic cell transplants, looking separately at slow wave EEG epochs versus global activation epochs. We found that both the crosscorrelation and the transfer entropy between the motor cortical EEG and basal ganglia LFPs was increased in the HP group (p<;0.05) and returned to normal levels in the grafted group, in most nuclei and conditions. However, the transfer entropy more robustly showed the difference between the groups. Our findings indicate that transfer entropy is a sensitive tool for nonlinear inter-nucleic functional connectivity analyses, and demonstrate the novel restorative ability of dopaminergic grafts for the parkinsonian basal ganglia electrophysiology.

Pathophysiology of Drug-Induced Dyskinesias

Christopher A. Lieu1,2, Vikram Shivkumar1, Timothy P. Gilmour1,2, Kala Venkiteswaran1,2, Mark J. Nolt1,3, Milind Deogaonkar4 and Thyagarajan Subramanian1,2 1Department of Neurology, The Pennsylvania State University College of Medicine and M.S. Hershey Medical Center, Hershey, Pennsylvania 2Department of Neural & Behavioral Sciences, The Pennsylvania State University College of Medicine and M.S. Hershey Medical Center, Hershey, Pennsylvania 3Functional Neurosurgical Services, Sentient, Inc., Hunt Valley, Maryland 4Center for Neurological Restoration, The Cleveland Clinic Foundation, Cleveland, Ohio USA

Commentary on - Human Embryonic Retinal Pigment Epithelial (Rpe) CellTransplants for Chronic Refractory Cocaine Addiction

Volume 4 • Issue 2 • 1000165 Health Care: Current Reviews ISSN: 2375-4273 HCCR, an open access journal Chronic refractory drug addiction remains a major cause of morbidity, mortality, and growing related healthcare expense in the United States. Therefore, a novel method of treatment for such severe refractory patients is required. Animal models of cocaine addiction using laboratory rats that self-administer the drug have a proven history of translational relevance. In the experiments describe in the recent publication, Venkiteswaran et al., we describe experiments where we examined cocaine seeking in rats following bilateral transplantation of human embryonic retinal pigment epithelial cells (hRPECs) or placebo into the nucleus accumbens (NAc) [l]. Human embryonic retinal pigment epithelial cells secrete the dopamine precursor, L-Dopa would be good to tell the reader what all they do here. The results showed that the out bred Sprague-Dawley male rats naturally segregated into two groups: one that self-administered a high amount of cocaine intravenously (IV) and a second group that self-administered a low amount of cocaine [2]. This finding is consistent with our previously published findings with cocaine and heroin and appears to reflect the individual differences seen in humans who abuse cocaine [3-5].