Parkinson Disease: US Pacific Zone

Chinta SJ, Andersen JK. · Buck Institute for Age Research, Novato, California 94945, USA. · Biochim Biophys Acta. · Pubmed #18358848 No free full text.

Abstract: Parkinson's disease (PD) is an adult-onset neurodegenerative disorder characterized by preferential loss of dopaminergic neurons in an area of the midbrain called the substantia nigra (SN) along with occurrence of intraneuronal inclusions called Lewy bodies. The majority of cases of PD are sporadic in nature with late onset (95% of patients); however a few PD cases (5%) are seen in familial clusters with generally earlier onset. Although PD has been heavily researched, so far the exact cause of the rather selective cell death is unknown. Multiple lines of evidence suggest an important role for oxidative stress. Dopaminergic neurons (DA) are particularly prone to oxidative stress due to DA metabolism and auto-oxidation combined with increased iron, decreased total glutathione levels and mitochondrial complex I inhibition-induced ROS production in the SN which can lead to cell death by exceeding the oxidative capacity of DA-containing cells in the region. Enhancing antioxidant capabilities and chelating labile iron pools in this region therefore constitutes a rational approach to prevent or slow ongoing damage of DA neurons. In this review, we summarize the various sources of reactive oxygen species that may cause redox imbalance in PD as well as potential therapeutic targets for attenuation of oxidative stress associated with PD.

Bartus RT, Herzog CD, Bishop K, Ostrove JM, Tuszynski M, Kordower JH, Gasmi M. · Ceregene, Inc., San Diego, CA 92121, USA. · Parkinsonism Relat Disord. · Pubmed #18267286 No free full text.

Abstract: PURPOSE: To develop CERE-120 (AAV-NTN) as a novel therapy for Parkinson's disease (PD) that might restore function of degenerating dopamine neurons and prevent further degeneration. SCOPE: A nonclinical program demonstrated that NTN expression can be predictably controlled following CERE-120 administration, provides clear evidence of efficacy in numerous animal models and is safe at dose multiples that far exceed those required for efficacy. Preliminary, open label evidence in PD subjects offers corroborative support for these observations. CONCLUSIONS: CERE-120 may represent an important, novel therapy for PD, though the clinical data require confirmation with additional clinical tests, including an ongoing multi-center, double-blinded controlled trial.

Rempe S, Hayden JM, Robbins RA, Hoyt JC. · Carl T. Hayden VA Medical Center, Research (RS/151), Building 27, 650 East Indian School Road, Phoenix, AZ 85012, USA. · Endocr Metab Immune Disord Drug Targets. · Pubmed #18220943 No free full text.

Abstract: Tetracycline and its derivatives, such as chlortetracycline, oxytetracycline, minocycline, doxycycline, methacycline and lymecycline, are naturally occurring or semi-synthetic polyketide compounds that exhibit a well known broad-spectrum antibacterial activity that interferes with prokaryotic protein synthesis at the ribosome level. In addition to this well known antibacterial activity these compounds also exhibit a variety of additional, less well known properties. Among them are separate and distinct anti-inflammatory properties. Tetracycline and related compounds have been shown to be effective chemotherapeutic agents in a wide variety of chronic inflammatory diseases and conditions. These include periodontitis, rosacea, acne, auto-immune diseases such as rheumatoid arthritis and protection of the central nervous system against trauma and neurodegenerative diseases such as stroke, multiple sclerosis and Parkinson disease. Tetracycline and related compounds appear to be beneficial for treatment of several chronic inflammatory airway diseases. Among them are asthma, bronchiectasis, acute respiratory distress syndrome, chemical induced lung damage and cystic fibrosis. The clinical use of tetracycline-type drugs in treatment of chronic airway inflammation is becoming a topic of intense interest. Recent findings in this area have led to an understanding of the myriad physiological, cellular and molecular mechanisms of the inflammatory response and how this response may be controlled to limit damage to host cells and tissues. This review presents a brief summary of the recent research in the area of tetracycline and its derivatives in control of pulmonary inflammation.

Zhang LN, Parkinson JF, Haskell C, Wang YX. · Department of Pharmacology and Immunology, Berlex Bioscience, Richmond, CA 94806, USA. · Curr Vasc Pharmacol. · Pubmed #18220938 No free full text.

Abstract: The murine carotid artery ligation (CAL) model has been widely used in the research of intimal hyperplasia, a major pathological process in vascular diseases, such as atherosclerosis and restenosis after angioplasty. Using a variety of gene knockout or transgenic mice and different pharmacological interventions, these studies have yielded significant new findings that contribute not only to unraveling the basic molecular mechanisms involved in the pathogenesis of intimal hyperplasia, but also to the identification of novel targets for intervention of these diseases. The current review outlines the findings derived from the murine CAL model, including studies run by the authors, covering the impacts of hyperlipidemia, pro-inflammatory factors, endothelial dysfunction, protease activity and growth mediators on neointimal hyperplasia.

Chen JJ, Swope DM. · Movement Disorders Center, Schools of Medicine and Pharmacy, Loma Linda University, Loma Linda, CA 92350, USA. · Pharmacotherapy. · Pubmed #18041936 No free full text.

Abstract: The available pharmacotherapies for Parkinson's disease address symptomatology because no agent has been demonstrated to provide definite neuroprotection against the disease. Choice of pharmacotherapy must include consideration of short-term benefits as well as long-term consequences. Patients with mild Parkinson's disease often function adequately without symptomatic treatment. However, recent data suggest that initiation of treatment with a well-tolerated agent (e.g., the monoamine oxidase [MAO]-B inhibitor rasagiline) in the absence of functional impairment is associated with improved long-term outcomes. Consideration should also be given to many patient-specific factors, including patient expectations, level of disability, employment status, functional as well as chronologic age, expected efficacy and tolerability of drugs, and response to previous Parkinson's disease therapies. Increasingly, initial monotherapy begins with a nondopaminergic agent or, if the patient is considered functionally young, a dopamine agonist. Since Parkinson's disease is a progressive disorder, adjustments to pharmacotherapy must be expected over time. When greater symptomatic relief is desired, or in the more frail elderly patient, levodopa therapy should be considered. If motor fluctuations develop, addition of a catechol-O-methyltransferase inhibitor or MAO-B inhibitor should be considered. For management of levodopa-induced dyskinesias, addition of amantadine is an option. Surgery may be considered when patients need additional symptomatic control or are experiencing severe motor complications despite pharmacologically optimized therapy.

Lew M. · Division of Movement Disorders, Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA. · Pharmacotherapy. · Pubmed #18041935 No free full text.

Abstract: This overview of Parkinson's disease is designed to serve as a background to the discussion elsewhere in this supplement on the pharmacotherapy used in its management. Parkinson's disease is a common progressive neurodegenerative condition associated with significant disability and negative impact on quality of life. Although the cause of Parkinson's disease is unknown, the pathologic manifestation involves the loss or dysfunction of dopaminergic neurons in the substantia nigra pars compacta. Characteristic clinical manifestations include difficulty with coordinated movement such as asymmetric resting tremor, rigidity, and bradykinesia. These symptoms and their response to levodopa constitute the basis for a clinical diagnosis of Parkinson's disease. Postural instability and gait abnormalities occur in more advanced disease. Although there is no cure for Parkinson's disease, a number of pharmacologic treatments are available for managing the motor and nonmotor symptoms. Research is under way to assess the disease-modifying ability of both standard and newer treatments.

Bhidayasiri R. · Chulalongkorn Comprehensive Movement Disorders Center, Chulalongkorn University Hospital, Bangkok, Thailand. · J Med Assoc Thai. · Pubmed #18041446 No free full text.

Abstract: Dementia represents the most common neurodegenerative disorders affecting approximately 5% of the elderly population over age 65 years. At present, different forms of dementia are distinguished, including Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal dementia, and dementia secondary to diseases, such as AIDS dementia. Unlike AD, these atypical dementias are often associated with neurological symptoms, reflecting the localization of the degenerative process rather than the nature of the underlying histopathology. The present article provides an overview of the clinical evaluation of patients with atypical dementia and reviews distinguishing features of atypical dementias that may be confused with AD. The laboratory and imaging evaluation of various types of dementias are described. Current practice guidelines and practice parameters are reviewed as relevant for primary care practitioner.

Martin JL, Ancoli-Israel S. · Veteran's Affairs Greater Los Angeles Healthcare System, Geriatric Research, Education and Clinical Center, 16111 Plummer Street, North Hills, CA 91343, USA. · Clin Geriatr Med. · Pubmed #18035230 links to  free full text

Abstract: Nighttime sleep disruption is characteristic of long-term care residents, is typically accompanied by daytime sleepiness, and may be caused by a multitude of factors. Causal factors include medical and psychiatric illness, medications, circadian rhythm abnormalities, sleep disordered breathing and other primary sleep disorders, environmental factors, and lifestyle habits. There is some suggestion that these factors are amenable to treatment; however, further research on the implementation of treatments within the long-term care setting is needed. Additional work is also needed to understand the administrative and policy factors that might lead to systemic changes in how sleep is viewed and sleep problems are addressed in long-term care settings.

Chen JJ, Swope DM, Dashtipour K. · Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Loma Linda University, Loma Linda, California 92350, USA. · Clin Ther. · Pubmed #18035186 No free full text.

Abstract: BACKGROUND: Inhibitors of monoamine oxidase (MAO) with selectivity and specificity for MAO type B (MAO-B) prolong the duration of action of both endogenously and exogenously derived dopamine. Rasagiline [N-propargyl-l(R)-aminoindan] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits brain MAO-B and is specifically designed for the treatment of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to review the pharmacology, tolerability, and clinical efficacy of rasagiline in the treatment of PD. METHODS: MEDLINE (1966-April 2007), the Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-April 2007) were searched for original research and review articles published in English. The search terms were monoamine oxidase, neuroprotection, Parkinson disease, propargylamine, rasagiline, and selegiline. The reference lists of articles were also consulted, as was information provided by the manufacturer of rasagiline. RESULTS: Data from 63 clinical and laboratory studies were analyzed. Based on the results from those studies, we concluded that rasagiline PO QD, at the therapeutic dosage range of 0.5 to 1 rag/d, is effective and well tolerated and completely, selectively, and specifically inhibited MAO-B. Pharmacologically, rasagiline was found to be < or =10-fold more potent than selegiline and was not metabolized to amphetamine derivatives. Rasagiline was effective both as monotherapy in early PD and as adjunctive treatment in patients with advancing PD and motor fluctuations. As monotherapy, rasagiline provided modest yet clinically meaningful benefit. A randomized, double-blind, placebo-controlled study found that, after 26 weeks of treatment, the adjusted effect size for total Unified Parkinson's Disease Rating Scale score was -4.20 (95% CI, -5.66 to -2.73) for rasagiline 1 mg/d versus placebo (P < 0.001). Preliminary long-term data from an open-label study suggest a sustained therapeutic advantage when rasagiline is initiated early (before the need for dopaminergic agents) rather than later. In patients with more advanced disease who received treatment with dopaminergic agents, rasagiline and entacapone were associated with reductions of "off" time significantly greater than placebo (-1.18 and -1.2 vs 0.4 hour; both, P < or = 0.001). Rasagiline was well tolerated in younger (aged <;70 years) and older (aged > or =70 years) patients with early or advanced PD. Pharmacologically, rasagiline has the potential to augment the vasopressor effects of diet-derived tyramine (ie, the "cheese reaction"). However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine. In experimental models, rasagiline has been found to have neuroprotective properties that may be independent of MAO-B inhibition. CONCLUSIONS: Based on this review, rasagiline has been found to be well tolerated and effective in the treatment of early PD and as adjunctive treatment in motor fluctuations. Whether rasagiline is associated with clinically significant neuroprotection (ie, disease modification) in PD is the subject of ongoing clinical trials.

Cummings J, Winblad B. · UCLA Alzheimer's Center, 10911 Weyburn Avenue, Suite 200, Los Angeles, CA 90095-7226, USA. · Expert Rev Neurother. · Pubmed #17997695 No free full text.

Abstract: Rivastigmine patch is the first transdermal treatment to be approved for Alzheimer's disease (AD) and Parkinson's disease dementia in the USA and for AD in Europe. It provides smooth, continuous drug delivery, and has the potential to maintain rivastigmine concentrations within an optimal therapeutic window while avoiding the peaks and troughs associated with oral drug delivery. The target dose, rivastigmine 9.5 mg/24 h patch (a 10 cm(2) patch), is given once daily and requires a simple one-step dose titration to the therapeutic dose. In a 24-week study in 1195 AD patients, the rivastigmine 9.5 mg/24 h patch provided similar efficacy to the highest dose range of capsules, with approximately three-times fewer reports of nausea and vomiting. Patients in the 9.5 mg/24 h patch and 12 mg/day capsule groups evidenced significant improvements versus placebo on both primary outcome measures: the Alzheimer's Disease Assessment Scale-Cognitive subscale; and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change; in addition to the following secondary outcome measures: Alzheimer's Disease Cooperative Study-Activities of Daily Living scale; Mini-Mental State Examination; and Trail Making Test Part A for assessment of attention, visual tracking and motor processing speed. Treatment differences on the Neuropsychiatric Inventory and Ten Point Clock-drawing Test did not reach statistical significance in this study. The patch may be the optimal way to treat dementia patients with rivastigmine.

Thompson SJ, Loftus LT, Ashley MD, Meller R. · RS Dow Neurobiology Laboratories, Legacy Clinical Research and Technology Center, 1225 Ne 2nd Avenue, Portland, OR 97232, USA. · Curr Opin Pharmacol. · Pubmed #17981502 links to  free full text

Abstract: The ubiquitin-proteasome system is the major non-lysosymal system for degrading proteins in the cell; the work leading to its discovery was awarded the Nobel Prize in Chemistry in 2004. In addition to small ubiquitin-like modifiers (e.g. Sumo and Nedd8), ubiquitin is involved in the complex regulation of the levels and function of many proteins and signaling pathways involved in determining cell fate. The cell death regulatory proteins, such as Bcl-2 family proteins and caspases are targeted for degradation by the ubiquitin proteasome system (UPS). In addition to mediating the degradation of proteins, the UPS regulates function and translocation of proteins, many of which play a role in the determination of cell fate. For example the UPS can regulate the activity of transcription factors, such as P53, NF-kappaB and HIF-1 alpha, which control the expression of protein mediators of cell death. Aberrant UPS function has been reported in multiple neuropathologies including Parkinson's diseases and ischemia. With the number of ubiquitin conjugating and de-conjugating enzymes reaching close to the levels of protein kinases and phosphatases, it is clear that ubiquitination is an important biological regulatory step for proteins.

Chesselet MF. · Department of Neurology and Neurobiology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA. · Exp Neurol. · Pubmed #17949715 links to  free full text

Abstract: Mutations in alpha-synuclein were the first genetic defect linked to Parkinson's disease (PD). The relevance of alpha-synuclein to sporadic PD is strongly supported by the presence of alpha-synuclein aggregates in neurons of patients. This has prompted the development of numerous animal models based on alpha-synuclein overexpression, primarily through genetic methods in mice and viral transduction in rats. In mice, different promoters and transgenes lead to a wide variety of phenotypes accompanied by non-existent, late onset, or non-specific neurodegeneration. Rapid neurodegeneration, in contrast, is observed after viral transduction but is limited to the targeted region and does not mimic the broad pathology observed in the disease. Overall, each model reproduces a subset of features of PD and can be used to identify therapeutic targets and test disease-modifying therapies. The predictive value of all models of the disease, however, remains speculative in the absence of effective neuroprotective treatments for PD in humans.

Boison D. · Legacy Research, R.S. Dow Neurobiology Laboratories, 1225 NE 2nd Avenue, Portland, OR 97232, USA. · Curr Opin Pharmacol. · Pubmed #17942368 No free full text.

Abstract: Adenosine is a modulator of brain function uniquely positioned to integrate excitatory and inhibitory neurotransmission. The past few years brought a wealth of new data fostering our understanding of how the adenosine system is involved in the pathogenesis of neurological diseases. Thus, dysregulation of the adenosine system is implicated in epileptogenesis and cell therapies have been developed to locally augment adenosine in an approach to prevent seizures. While activation of inhibitory adenosine A(1) receptors is beneficial in epilepsy, chronic pain and cerebral ischemia, inhibition of facilitatory A(2A) receptors has profound neuroprotective effects, which are currently exploited in clinical trials in Parkinson's disease. A new era of adenosine-based therapies has begun, with the prospect to cover a wide range of neurological diseases.

Fiandaca M, Forsayeth J, Bankiewicz K. · Department of Neurological Surgery, Movement Disorder Research Program, University of California, Mission Center Building, San Francisco, CA 94103, USA. · Exp Neurol. · Pubmed #17920059 No free full text.

Abstract: The incidence of Parkinson's disease (PD) increases greatly with age, and the baby-boomer population can expect to generate a large number of individuals with the disease, all of whom will have significantly increased medical care needs over periods of 20 years or more. This emerging healthcare burden to our society calls for accelerated efforts to understand this disease better and treat it more effectively. The growing interest in gene therapy grew out of a recognition that new medicines may be needed to combat the relentless progression of the disease in the face of conventional pharmaco-therapies and surgical interventions that have so far failed to offer more than palliative relief. The potential of gene therapy to alter dramatically the course of the disease lies very much with the challenge of converting a research tool into a medical option, a process that clearly requires a unique combination of rigor and flexibility. In this review, we examine the unique aspects of gene therapy that make its use in PD attractive, but also analyze the difficulties of employing a medicine that acts for the rest of the patient's life.

Bhidayasiri R, Truong DD. · Chulalongkorn Comprehensive Movement Disorders Center, Division of Neurology, Chulalongkorn University Hospital, Bangkok 10330, Thailand. · J Neurol Sci. · Pubmed #17897677 No free full text.

Abstract: 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.

Henderson VW. · Department of Health Research and Policy, Stanford University, Stanford, California 94305-5405, United States. · Climacteric. · Pubmed #17882682 No free full text.

Abstract: Menopausal status and estrogen-containing hormone therapy may influence several neurological disorders, including Alzheimer's disease, epilepsy, migraine headache, multiple sclerosis, Parkinson's disease, sleep disorders, and stroke. For most of these illnesses, evidence on hormone therapy is insufficient to guide practice decisions. For stroke, clinical trial evidence indicates that hormone therapy increases risk of cerebral infarction. For women with Alzheimer's disease, estrogen treatment trials have tended to be small and of short duration. Most suggest that estrogen started after the onset of dementia symptoms does not meaningfully improve cognition or slow disease progression. Hormone therapy initiated after age 64 increased all-cause dementia in the Women's Health Initiative Memory Study. Many observational studies, however, report protective associations between hormone use and Alzheimer risk. Apparent risk reduction may represent a bias toward hormone therapy, since hormones are more often prescribed to healthier women. However, when compared to the Women's Health Initiative Memory Study, estrogen exposures in many observational studies reflect hormone initiation at a younger age, closer to the time of menopause. One intriguing hypothesis is that hormone therapy initiated or used during an early critical window may reduce later Alzheimer incidence. Public health implications of this hypothesis are important, but current data are inadequate to decide the issue.

Rockenstein E, Crews L, Masliah E. · Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0624, USA. · Adv Drug Deliv Rev. · Pubmed #17869376 No free full text.

Abstract: Neurodegenerative disorders of the aging population affect over 5 million people in the US and Europe alone. The common feature is the progressive accumulation of misfolded proteins with the formation of toxic oligomers. Previous studies show that while in Alzheimer's disease (AD) misfolded amyloid-beta protein accumulates both in the intracellular and extracellular space, in Lewy body disease (LBD), Parkinson's disease (PD), Multiple System Atrophy (MSA), Fronto-Temporal dementia (FTD), prion diseases, amyotrophic lateral sclerosis (ALS) and trinucleotide repeat disorders (TNRD), the aggregated proteins accumulate in the plasma membrane and intracellularly. Protein misfolding and accumulation is the result of an altered balance between protein synthesis, aggregation rate and clearance. Based on these studies, considerable advances have been made in the past years in developing novel experimental models of neurodegenerative disorders. This has been in part driven by the identification of genetic mutations associated with familial forms of these conditions and gene polymorphisms associated with the more common sporadic variants of these diseases. Transgenic and knock out rodents and Drosophila as well as viral vector driven models of Alzheimer's disease (AD), PD, Huntington's disease (HD) and others have been developed, however the focus for this review will be on rodent models of AD, FTD, PD/LBD, and MSA. Promising therapeutic results have been obtained utilizing amyloid precursor protein (APP) transgenic (tg) models of AD to develop therapies including use of inhibitors of the APP-processing enzymes beta- and gamma-secretase as well as vaccine therapies.

Truong DD, Bhidayasiri R, Wolters E. · The Parkinson's and Movement Disorder Institute, 9940 Talbert Avenue, Fountain Valley, CA 92708, USA. · J Neurol Sci. · Pubmed #17804018 No free full text.

Abstract: Progress in pharmacology has markedly improved the treatment of early Parkinson's disease. The management of advanced Parkinson's 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.

Chen JJ, Fernandez HH. · Movement Disorders Center, Schools of Medicine and Pharmacy, Loma Linda University, Loma Linda, California 92350, USA. · Drugs Aging. · Pubmed #17702535 No free full text.

Abstract: Parkinson's disease affects up to 1 million people in the US, most of them elderly. Motor and non-motor symptoms can be significantly disabling to the point of necessitating institutionalisation. Age-related changes in drug absorption, distribution, metabolism and excretion complicate the treatment of elderly patients with Parkinson's disease. General management principles include initiation of medication at low doses with gradual titration based on clinical effects, avoidance of certain classes of drugs (e.g. anticholinergics), and attention to polypharmacy and its risk for potentially toxic drug interactions. Levodopa remains the most efficacious anti-Parkinson's disease medication and should be the cornerstone of therapy in the elderly Parkinson's disease patient. Use of dopamine receptor agonists, amantadine and anticholinergic drugs in the elderly is limited by high risk for psychotoxicity. Catechol-O-methyltransferase inhibitors may be used to augment levodopa in the setting of 'wearing off' (i.e. motor fluctuations). Monoamine oxidase type B (MAO-B) inhibitors can be used across the spectrum of disease severity, but selegiline (deprenyl), the prototype in this class, is characterised by low and erratic bioavailability of the parent drug and conversion to amphetamine metabolites that may increase the risk of adverse events. A new orally disintegrating tablet formulation overcomes some of these limitations. Rasagiline is a new, selective, second-generation MAO-B inhibitor that is chemically and metabolically distinct from selegiline. The favourable safety profile of rasagiline in the elderly and its once-daily formulation may maximise drug adherence and improve outcomes.

Rogers J, Mastroeni D, Leonard B, Joyce J, Grover A. · The L. J. Roberts Center for Alzheimer's Research, Sun Health Research Institute Sun City, Arizona 85351, USA. · Int Rev Neurobiol. · Pubmed #17678964 No free full text.

Abstract: Microglial activation similar to that which occurs in peripheral macrophages during inflammatory attack was first demonstrated in the Alzheimer's disease (AD) brain two decades ago. Localization to pathologically vulnerable regions of AD cortex, localization to sites of specific AD pathology such as amyloid-beta peptide (Abeta) deposits, and the ability of activated microglia to release toxic inflammatory factors suggested that the activation of microglia in AD might play a pathogenic role. However, proving this hypothesis in a disease in which so many profound pathologies occur (e.g., Abeta deposition, neurofibrillary tangle formation, inflammation, neuronal loss, neuritic loss, synaptic loss, neuronal dysfunction, vascular alterations) has proven difficult. Although investigations of microglia in Parkinson's disease (PD) are more recent and therefore less extensive, demonstration of a pathogenic role for microglial activation may actually be much simpler in PD than AD because the root pathological event in PD, loss of dopamine (DA)-secreting substantia nigra neurons, is already well established. Indeed, indirect but converging evidence of a pathogenic role for activated microglia in PD has already begun to emerge. The nigra reportedly has the highest density of microglia in brain, and, in PD, nigral microglia are not only highly activated but also highly clustered around dystrophic DA neurons. 6-OHDA and MPTP models of PD in rodents induce substantia nigra microglial activation. More cogent, injections of the classic microglial/macrophage activator lipopolysaccharide into or near the rodent nigra cause a specific loss of DA neurons there. Culture models with human microglia and human cellular targets replicate this phenomenon. Notably, nearly all the proposed etiologies of PD, including brain bacterial and viral exposure, pesticides, drug contaminants, and repeated head trauma, are known to cause brain inflammation. A mechanism by which activated microglia might specifically target DA neurons remains a critical missing link in the proof of a pathogenic role for activated microglia in PD. If such a link could be established, however, clinical intervention trials with agents that dampen microglial activation might be warranted in PD.

Lipton SA, Gu Z, Nakamura T. · Neuroscience and Aging Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA. · Int Rev Neurobiol. · Pubmed #17678953 No free full text.

Abstract: Inflammatory mediators, including free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), can contribute to neurodegenerative diseases in part by triggering protein misfolding. In this chapter, we will discuss a newly discovered pathway for this phenomenon and possible novel treatments. Excitotoxicity, defined as overstimulation of glutamate receptors, has been implicated in a final common pathway contributing to neuronal injury and death in a wide range of acute and chronic neurological disorders, ranging from Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Alzheimer's disease (AD) to stroke and trauma. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, leading to excessive Ca(2+) influx through the receptor's associated ion channel and subsequent free radical production, including NO and ROS. These free radicals can trigger a variety of injurious pathways, but newly discovered evidence suggests that some proteins are S-nitrosylated (transfer of NO to a critical thiol group), and this reaction can mimic the effect of rare genetic mutations. This posttranslational modification can contribute to protein misfolding, triggering neurodegenerative diseases. One such molecule affected is protein disulfide isomerase (PDI), an enzyme responsible for normal protein folding in the endoplasmic reticulum (ER). We found that when PDI is S-nitrosylation (forming SNO-PDI), the function of the enzyme is compromised, leading to misfolded proteins and contributing to neuronal cell injury and loss. Moreover, SNO-PDI occurs at pathological levels in several human diseases, including AD and PD. This discovery thus links protein misfolding to excitotoxicity and free radical formation in a number of neurodegenerative disorders. Another molecule whose S-nitrosylation can lead to abnormal protein accumulation is the E3 ubiquitin ligase, parkin, which contributes to the pathogenesis of PD. One way to ameliorate excessive NO production and hence abnormal S-nitrosylations would be to inhibit NMDA receptors. In fact, blockade of excessive NMDA receptor activity can in large measure protect neurons from this type of injury and death. However, inhibition of the NMDA receptor by high-affinity antagonists also blocks the receptor's normal function in synaptic transmission and leads to unacceptable side effects. For this reason, many NMDA receptor antagonists have disappointingly failed in advanced clinical trials. Our group was the first to demonstrate that gentle blockade of NMDA receptors by memantine, via a mechanism of uncompetitive open-channel block with a rapid "off-rate," can prevent this type of damage in a clinically efficacious manner without substantial side effects. For these Uncompetitive/Fast Off-rate therapeutics, we use the term "UFO drugs" because like Unidentified Flying Objects, they leave very quickly as soon as their job is finished. As a result, memantine blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this by preferentially entering the receptor-associated ion channel when it is excessively open, and, most importantly, when its off-rate from the channel is relatively fast so that it does not accumulate to interfere with normal synaptic transmission. Hence, memantine is clinically well tolerated, has been used in Europe for PD for many years, and recently passed multiple phase III trials for dementia, leading to its approval by the FDA and European Union for moderate-to-severe AD. Clinical studies of memantine for additional neurological disorders, including other dementias, neuropathic pain, and glaucoma, are underway. We have also developed a series of second-generation drugs that display greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites, including critical thiol groups that are S-nitrosylated. In this case, in contrast to PDI or parkin, S-nitrosylation proves to be neuroprotective by decreasing excessive NMDA receptor activity. Targeted S-nitrosylation of the NMDA receptor can be achieved by coupling NO to memantine, yielding second-generation "UFO drugs" known as NitroMemantines.

Cummings J, Lefèvre G, Small G, Appel-Dingemanse S. · UCLA Alzheimer's Center, Los Angeles, CA 90095-7226, USA. · Neurology. · Pubmed #17646618 No free full text.

Abstract: The dual cholinesterase inhibitor rivastigmine is approved in capsule form in many countries for the symptomatic treatment of dementia associated with Alzheimer disease (AD) and Parkinson disease (PD). All orally administered cholinesterase inhibitors are associated with central cholinergic gastrointestinal side effects, particularly during the titration phase, which are believed to be caused by a rapid increase in brain acetylcholine levels after effective inhibition of the target enzymes. A recently developed rivastigmine transdermal patch may have the potential to reduce such side effects. Pharmacokinetic studies have shown that transdermal administration of rivastigmine prolongs t(max), lowers C(max), and reduces fluctuations in plasma concentration. The 10-cm(2) rivastigmine patch provides comparable exposure (area under the curve, AUC) to the highest capsule dose (6-mg BID) and may be the target maintenance dose for most patients, delivering optimal rivastigmine exposure to produce a therapeutic effect. The potential of a patch to improve the tolerability of rivastigmine (e.g., nausea and vomiting) while permitting similar exposure to the highest doses of capsules may, in turn, lead to improved efficacy and compliance.

Quik M, Bordia T, O'Leary K. · The Parkinson's Institute, Sunnyvale, CA 94089, USA. · Biochem Pharmacol. · Pubmed #17631864 links to  free full text

Abstract: Parkinson's disease is a debilitating neurodegenerative movement disorder characterized by damage to the nigrostriatal dopaminergic system. Current therapies are symptomatic only and may be accompanied by serious side effects. There is therefore a continual search for novel compounds for the treatment of Parkinson's disease symptoms, as well as to reduce or halt disease progression. Nicotine administration has been reported to improve motor deficits that arise with nigrostriatal damage in parkinsonian animals and in Parkinson's disease. In addition, nicotine protects against nigrostriatal damage in experimental models, findings that have led to the suggestion that the reduced incidence of Parkinson's disease in smokers may be due to the nicotine in tobacco. Altogether, these observations suggest that nicotine treatment may be beneficial in Parkinson's disease. Nicotine interacts with multiple nicotinic receptor (nAChR) subtypes in the peripheral and central nervous system, as well as in skeletal muscle. Work to identify the subtypes affected in Parkinson's disease is therefore critical for the development of targeted therapies. Results show that striatal alpha6beta2-containing nAChRs are particularly susceptible to nigrostriatal damage, with a decline in receptor levels that closely parallels losses in striatal dopamine. In contrast, alpha4beta2-containing nAChRs are decreased to a much smaller extent under the same conditions. These observations suggest that development of nAChR agonists or antagonists targeted to alpha6beta2-containing nAChRs may represent a particularly relevant target for Parkinson's disease therapeutics.

Khandhar SM, Marks WJ. · Northern California Kaiser Permanente, Surgical Movement Disorders Program, San Francisco, California, USA. · Dis Mon. · Pubmed #17586326 No free full text.

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Sheldahl LC, Marriott LK, Bryant DM, Shapiro RA, Dorsa DM. · Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97236, USA. · Minerva Endocrinol. · Pubmed #17557034 No free full text.

Abstract: Estrogen is neuroprotective in a large number of models in vivo and in vitro. Its application in hormone replacement therapy has proven to be more complicated, necessitating better understanding of how estrogen signals in the brain. Estrogen binds to estrogen receptors to regulate gene transcription, and activates a number of rapid signaling cascades from the plasma membrane. These rapid signaling cascades have been shown to play important roles in mediating the neuroprotective effects of estrogen. This review covers evidence that understanding and targeting the membrane effects of estrogen has emerged as an important area in the design of novel neuroprotective drugs.