Daniel D. Truong

Expanding use of botulinum toxin.

Botulinum toxin type A (BTX-A) is best known to neurologists as a treatment for neuromuscular conditions such as dystonias and spasticity and has recently been publicized for the management of facial wrinkles. The property that makes botulinum toxin type A useful for these various conditions is the inhibition of acetylcholine release at the neuromuscular junction. Although botulinum toxin types A and B (BTX-A and BTX-B) continue to find new uses in neuromuscular conditions involving the somatic nervous system, it has also been recognized that the effects of these medications are not confined to cholinergic neurons at the neuromuscular junction. Acceptors for BTX-A and BTX-B are also found on autonomic nerve terminals, where they inhibit acetylcholine release at glands and smooth muscle. This observation led to trials of botulinum neurotoxins in various conditions involving autonomic innervation. The article reviews the emerging use of botulinum neurotoxins in these and selected other conditions, including sialorrhea, primary focal hyperhidrosis, pathological pain and primary headache disorders that may be of interest to neurologists and related specialists.

Management of non-motor symptoms in advanced Parkinson disease

Progress in pharmacology has markedly improved the treatment of early Parkinsons disease. The management of advanced Parkinsons symptoms, however, remains a challenge. These symptoms are divided into motor and non-motor symptoms. Non-motor symptoms may appear early or late in the disease and sometimes even before the onset of the first motor symptoms confirming the diagnosis. The spectrum of non-motor symptoms encompasses autonomic dysfunctions, sleep disorders, mood disorders, impulse control disorders, cognitive dysfunction, dementia, paranoia and hallucinations. They are often less appreciated than motor symptoms but are important sources of disability for many PD patients. This review describes these non-motor symptoms and their managements.

Activation of adenosine triphosphate-sensitive potassium channels confers protection against rotenone-induced cell death: therapeutic implications for Parkinson's disease.

It is anticipated that further understanding of the protective mechanism induced by ischemic preconditioning will improve prognosis for patients of ischemic injury. It is not known whether preconditioning exerts beneficial actions in neurodegenerative diseases, in which ischemic injury plays a causative role. Here we show that transient activation of ATP‐sensitive potassium channels, a trigger in ischemic preconditioning signaling, confers protection in PC12 cells and SH‐SY5Y cells against neurotoxic effect of rotenone and MPTP, mitochondrial complex I inhibitors that have been implicated in the pathogenesis of Parkinsons disease. The degree of protection is in proportion to the bouts of exposure to an ATP‐sensitive potassium channel opener, a feature reminiscent of ischemic tolerance in vivo. Protection is sensitive to a protein synthesis inhibitor, indicating the involvement of de novo protein synthesis in the protective processes. Pretreatment of PC12 cells with preconditioning stimuli FeSO4 or xanthine/xanthine oxidase also confers protection against rotenone‐induced cell death. Our results demonstrate for the first time the protective role of ATP‐sensitive potassium channels in a dopaminergic neuronal cell line against rotenone‐induced neurotoxicity and conceptually support the view that ischemic preconditioning‐derived therapeutic strategies may have potential and feasibility in therapy for Parkinsons disease.

Motor complications in Parkinson disease: clinical manifestations and management.

Long-term dopaminomimetic therapy, not limited to levodopa, is complicated by the emergence of variations of motor response in a majority of Parkinson disease (PD) patients. These variations can occur in different forms, as early wearing off during the initial stage of motor complications, dyskinesias in the intermediate stage, and complex fluctuations in the advanced stage. Considered to be a major source of disability in advanced PD patients, recognition of these complications is critical in order to develop different strategies designed not only to treat these problems when they develop, but also to prevent troublesome complications associated with potential risk factors. In this article, authors classify a wide clinical spectrum of motor complications into different stages as the disease progresses through the treatment. A number of strategies are proposed in order to manage these complications as well as to avoid them. Better understanding of these potential complications will result in better management of these problems and lessen the disability associated with advanced PD.

(-)-Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, reduces dichlorodiphenyl-trichloroethane (DDT)-induced cell death in dopaminergic SHSY-5Y cells.

Results from epidemiological studies indicated that there exists an inverse correlation between consumption of green tea and neurodegenerative diseases including Parkinsons disease. We hypothesized that consumption of green tea would activate endogenous protective mechanisms against environmental toxin-induced cell injury, which is believed to play a causative role in the etiology of Parkinsons disease. Here, we found that epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, concentration-dependently (1 microM, 3 microM and 10 microM) reduced dichlorodiphenyl-trichloroethane (DDT) (100 microM)-induced cell death in dopaminergic neuroblastoma SHSY-5Y cells. The cell viability was determined by trypan blue exclusion assays. We also found that preconditioning the SHSY-5Y cells with EGCG by multiple, brief, prior exposures of the cells to EGCG can subsequently protect the cells from DDT-induced cell death. The EGCG-induced protective effect positively correlated with the number of exposures to EGCG. These results suggest that EGCG has a protective effect against DDT-induced cell death, and that prior exposures to EGCG activate an endogenous protective mechanism in the dopaminergic cells which can mitigate organochlorine pesticide-induced cell injury.

Therapeutic strategies for nonmotor symptoms in early Parkinson's disease: the case for a higher priority and stronger evidence.

It is now recognized that the neuropathology of early Parkinsons disease (PD) is not limited to the nigrostriatal dopaminergic system, but also involves various brainstem nuclei, the hypothalamus, the olfactory system, and the peripheral autonomic nervous system. Given the disseminated neuropathology of early PD, the earliest clinical signs include a myriad of non-motor manifestations including sleep-wake cycle regulation, cognition, mood and motivation, olfactory and gustatory functions, autonomic functions, and sensory and pain processing. Despite this realization, there is clearly a paucity of trials that have systematically evaluated the treatment of non-motor symptoms of PD in the early stages. For example, only one large-scale, placebo-controlled randomized trial has been conducted on the treatment of depression in PD patients. There are no reports of randomized controlled trials of therapeutic agents looking at the frequently reported anxiety and fatigue in early PD patients. Based on this lack of evidence, therapy for early non-motor manifestations is often ignored and the focus remains on dopamine replacement strategies with main outcomes being restricted to motor measurements, such as the Unified Parkinsons Disease Rating Scale. This article presents the case for prioritizing well-designed, controlled clinical trials of therapeutic interventions focusing on non-motor symptoms in early PD patients.

Ketogenic diet prevents seizure and reduces myoclonic jerks in rats with cardiac arrest-induced cerebral hypoxia

Although the mechanism underlying the anti-epileptic effects of a ketogenic diet (KD) is not known, KD is reported to be an effective treatment for intractable epilepsy, in particular among children. Here, we evaluated whether a KD can reduce posthypoxic seizure and myoclonic jerks in a rat model of cardiac arrest-induced cerebral hypoxia. In this study, rats were divided into two groups: one group received a normal diet while the other group was fed a KD for 25 days before being subjected to cardiac arrest-induced cerebral hypoxia. We found that rats fed a normal diet developed seizures and severe myoclonic jerks in response to auditory stimuli after the hypoxic insults, whereas the rats on the KD did not develop seizure and showed much less severe myoclonic jerks in response to auditory stimuli. The results suggested that the KD has beneficial effects against posthypoxic seizure and myoclonus.

NMDA receptor-mediated excitotoxicity contributes to the cerebral hypoxic injury of a rat model of posthypoxic myoclonus

Cardiac arrest-induced cerebral hypoxic injury could induce posthypoxic movement disorders. Here we investigated the effects of memantine, an NMDA receptor channel blocker, on the neurodegeneration occurred in an established rat model of posthypoxic myoclonus. We found that administration of memantine for 7 days significantly reduced cerebral hypoxia-induced neurodegeneration in the CA1 of the hippocampus, the reticular thalamic nucleus (RTN) and the primary fissure of the cerebellum of the posthypoxic animals. The results suggest that the neurodegeneration observed in specific areas of the brain of the posthypoxic rats is contributed by NMDA receptor-mediated excitotoxicity.

Post-hypoxic myoclonus induces Fos expression in the reticular thalamic nucleus and neurons in the brainstem

Post-hypoxic myoclonus is a movement disorder characterized by brief, sudden involuntary muscle jerks. Although the mechanism underlying this disorder remains unclear, earlier pharmacological studies indicated that aberrant activity of specific neuronal circuitry in the central nervous system causes this disorder. In the present study, Fos protein, an immediate-early gene product, was used as a marker of neuronal activity to identify the brain nuclei possibly involved in post-hypoxic myoclonus. We found that Fos protein was immunologically detected in the reticular thalamic nucleus (RT), the medial longitudinal fasciculus (MLF) as well as in the locus coeruleus (LC) and the periventricular gray substance (PVG) in post-hypoxic rats that developed myoclonus in response to auditory stimuli. Fos was not detected in these nuclei from rats that underwent 4 min of cardiac arrest without myoclonus. Electrolytic lesions of the RT or MLF but not the LC/PVG significantly reduced auditory stimulated myoclonus in the post-hypoxic rats. The results suggest that neuronal activity in the RT and the MLF plays a contributing role in post-hypoxic myoclonus.

Amiloride but Not Memantine Reduces Neurodegeneration, Seizures and Myoclonic Jerks in Rats with Cardiac Arrest-Induced Global Cerebral Hypoxia and Reperfusion

It has been reported that both activation of N-methyl-D-aspartate receptors and acid-sensing ion channels during cerebral ischemic insult contributed to brain injury. But which of these two molecular targets plays a more pivotal role in hypoxia-induced brain injury during ischemia is not known. In this study, the neuroprotective effects of an acid-sensing cation channel blocker and an N-methyl-D-aspartate receptor blocker were evaluated in a rat model of cardiac arrest-induced cerebral hypoxia. We found that intracisternal injection of amiloride, an acid-sensing ion channel blocker, dose-dependently reduced cerebral hypoxia-induced neurodegeneration, seizures, and audiogenic myoclonic jerks. In contrast, intracisternal injection of memantine, a selective uncompetitive N-methyl-D-aspartate receptor blocker, had no significant effect on cerebral hypoxia-induced neurodegeneration, seizure and audiogenic myoclonic jerks. Intracisternal injection of zoniporide, a specific sodium-hydrogen exchanger inhibitor, before cardiac arrest-induced cerebral hypoxia, also did not reduce cerebral hypoxia-induced neurodegeneration, seizures and myoclonic jerks. These results suggest that acid-sensing ion channels play a more pivotal role than N-methyl-D-aspartate receptors in mediating cerebral hypoxia-induced brain injury during ischemic insult.