Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The initial benefits of levodopa decline for as many as half of all patients with Parkinson's disease treated for 2 years or more. Although levodopa is the most effective means for symptom relief, many parkinsonian patients lose the consistency of optimal symptom control. The variability experienced by such patients may arise from several alternative mechanisms at the level of the central nervous system (e.g., a narrowed therapeutic window for receptor-mediated effects or the loss of storage capability for dopamine in the parkinsonian brain). Whatever the cause, several practical methods have been developed. Dopaminergic agonists have played a major role in improving such problem. There are also several strategies for enhancing levodopa's dose by dose effectiveness, including sustained-release levodopa preparations and enteral infusions of levodopa. Another approach is the use of selegiline (deprenyl), MAO-B inhibitor slowing the breakdown of dopamine and thereby extending the duration of levodopa effect. Although selegiline can lessen the abruptness of levodopa wearing off, it can also exacerbate undesired peak effects of the drug. Clinical trials are planned with levodopa pro-drugs and inhibitors of catechol-O-methyltransferase to learn if these approaches can improve problems of long-term levodopa therapy.
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PMID:Treatment strategies for extension of levodopa effect. 158 87

We have recently cloned the neurotensin receptor from human substantia nigra. Using in situ hybridization techniques, with an 35S-labeled antisense RNA probe complementary to this receptor complementary DNA, we studied the expression of the human neurotensin receptor in the brain from control and Parkinson's disease subjects. We also performed an analogous study with rat brain. Neurotensin receptor messenger RNA was present in high levels in melanized neurons of the substantia nigra pars compacta and the nucleus paranigralis (the ventral tegmental area for rat brain). Background levels of signals for neurotensin receptor messenger RNA were detected in the nucleus ruber, the colliculus inferior and the striatal subdivisions (the nucleus caudatus, the putamen and the nucleus accumbens) of both human and rat brain. All these areas, except the nucleus ruber and the collicus inferior, contain very high to high levels of neurotensin receptor binding sites. Additionally, Parkinson's disease brains had markedly fewer melanized (possibly dopaminergic) neurons, as expected, and correspondingly very low or background levels of messenger RNA for neurotensin receptor. We have also demonstrated heterogeneity among the melanized cells expressing messenger RNA encoding the neurotensin receptor in the substantia nigra and the nucleus paranigralis of human brain. The neurons in the nucleus paranigralis had lower melanin pigmentation and higher expression of neurotensin receptor messenger RNA. In general, the expression of the messenger RNA within the highly and evenly melanized neurons was lower than that found in low or unevenly pigmented neurons. The neurons in the nucleus paranigralis had lower melanin pigmentation and higher expression of neurotensin receptor messenger RNA. The low pigmented neurons in the ventral tier of the substantia nigra had relatively high expression. On the other hand, highly and evenly melanized neurons in these regions of the brain had low expression of neurotensin receptor messenger RNA. Together with the previous binding data, it is suggested that not only in rat brain, but also in human brain, melanized (possibly dopaminergic) neurons in the substantia nigra and the nucleus paranigralis (ventral tegmental area of rat brain) synthesize neurotensin receptors and express them in their perikarya and the terminal regions. Additionally, the heterogeneity of the melanized neurons in human brain may play a role in the normal function of dopaminergic systems and probably in the etiology of some neurological and psychiatric disorders.
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PMID:Heterogeneity of melanized neurons expressing neurotensin receptor messenger RNA in the substantia nigra and the nucleus paranigralis of control and Parkinson's disease brain. 770 May 29

Traumatic brain injury (TBI) is found in many sports. A mild head injury (concussion of brain) is found in more than 80%, mainly in sports with contact to others. Especially affected by death are air sports, horse riding and cycling, whereby brain damage often is the leading injury. With the example of a cycling accident the possible processing dynamics of a mild head injury with secondary brain damage through an intracranial hematoma is demonstrated in the following. For the assessment of sports ability, there is often made the division with symptoms as confusion, amnesia and unconsciousness after a mild head injury (scale 1-3). According to the gravitational scale of cerebral concussion, an adequate sports break should be kept. Postcommotional symptoms prove sports inability. A chronic brain damage is not rarely found in some combative sports. In this case the injury may result in a traumatic encephalopathia with the evaluation of dementia and in some cases also Parkinson's disease is observed. To prevent a TBI there should be worn an adequate protective headgear especially by children in training and in sports contests concerning risk sports. Further recommendations for prevention are presented and with them there will also be responded to sports ability in neurosurgical diseases.
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PMID:[Craniocerebral trauma in sports. With recommendations for prevention]. 1040 62

It has been known for over 30 years that olfactory function is disordered in idiopathic Parkinson's disease (IPD). The severity and partial specificity of anosmia was not realized until recently, with the advent of more detailed analysis and sophisticated measurement. The olfactory vector hypothesis suggests that the causative agent for IPD enters the brain via the nasal route, but the reason for olfactory dysfunction may be more subtle. Evidence for olfactory disturbance is reviewed from pathological, psychological, neurophysiological and genetic stand-points. It is proposed that the initial causative event in IPD may start in the rhinencephalon (olfactory brain) prior to damage in the basal ganglia.
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PMID:Is Parkinson's disease a primary olfactory disorder? 1062 64

This review examines interactions in the mammalian central nervous system (CNS) between carnosine and the endogenous transition metals zinc and copper. Although the relationship between these substances may be applicable to other brain regions, the focus is on the olfactory system where these substances may have special significance. Carnosine is not only highly concentrated in the olfactory system, but it is also contained in neurons (in contrast to glia cells in most of the brain) and has many features of a neurotransmitter. Whereas the function of carnosine in the CNS is not well understood, we review evidence that suggests that it may act as both a neuromodulator and a neuroprotective agent. Although zinc and/or copper are found in many neuronal pathways in the brain, the concentrations of zinc and copper in the olfactory bulb (the target of afferent input from sensory neurons in the nose) are among the highest in the CNS. Included in the multitude of physiological roles that zinc and copper play in the CNS is modulation of neuronal excitability. However, zinc and copper also have been implicated in a variety of neurologic conditions including Alzheimer's disease, Parkinson's disease, stroke, and seizures. Here we review the modulatory effects that carnosine can have on zinc and copper's abilities to influence neuronal excitability and to exert neurotoxic effects in the olfactory system. Other aspects of carnosine in the CNS are reviewed elsewhere in this issue.
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PMID:Interactions between carnosine and zinc and copper: implications for neuromodulation and neuroprotection. 1095 Oct 99

MacLean's pioneering concept of "The Triune Brain" began to emerge in 1949 with his publication Psychosomatic disease and the "visceral brain", followed in 1952 by Some psychiatric implications of physiological studies on frontotemporal portion of limbic system (visceral brain). This shows that his seminal ideas grew out of his astute observation of psychiatric signs and symptoms. Later on, he observed the broad spectrum of human epileptic seizures and its cause in the limbic system. A large variety of uncontrolled feelings and emotions, together with bizarre motor behavior, is elicited by seizures in the hippocampus and other limbic structures.Meanwhile, based on the triune brain model, a new approach to psychopathology has taken shape. It is the evolutionary perspective of mental diseases such as the major psychoses, anorexia nervosa, anxiety disorders, and also brain diseases such as Parkinson's disease or Huntington's disease. Many mental illnesses are marked by severe deficits in social behavior and social communication. The social communication system disintegrates, especially in the major psychoses. The response choices to social or other external signals in a given situation become limited or even distorted, and reasoning is no longer part of decision making. The emphasis of this contribution is on the disintegration of social behavior in psychopathology, based on evolutionary psychiatry. MacLean's concept provides valuable insight for understanding the biological roots of human social behavior and communication. It is time to uncover the ties between the natural and the social sciences.
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PMID:The place of the Triune Brain in psychiatry. 1295 43

Neurturin (NTN) is a neurotrophic factor for dopaminergic neurons that may be therapeutic for patients with Parkinson's disease (PD). As a crucial component in a series of nonclinical translational studies aimed at testing whether CERE-120 should advance into clinical trials in PD subjects, we characterized the expression, bioactivity and safety of CERE-120, an adeno-associated virus type-2 (AAV2) vector encoding NTN, following delivery to the striatum of nonhuman primates. Monkeys received bilateral injections of CERE-120 across a tenfold range of doses (6 x 10(10) to 6 x 10(11) vector genomes per animal) or formulation buffer (FB) control. We report here, for the first time, a dose-related: increase in NTN protein expression within the striatum and substantia nigra (SN) pars compacta of nonhuman primates; increase in nigrostriatal tyrosine hydroxylase (TH), (the rate-limited enzyme for dopamine); and activation of phosphorylated signal-regulated kinase (a common neurotrophic signaling event). Additionally, extensive toxicology testing revealed no adverse effects of CERE-120 on in-life measures, neurotoxicity (in any site throughout the brain) or systemic pathology (in any organ or tissue) across the tenfold range of doses. Collectively, these data provide substantial novel evidence for the potential utility of CERE-120 as a novel treatment for PD and support ongoing clinical trials testing CERE-120 in PD patients.
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PMID:Transgene expression, bioactivity, and safety of CERE-120 (AAV2-neurturin) following delivery to the monkey striatum. 1872 39

CNS neuronal networks are known to control normal physiological functions, including locomotion and respiration. Neuronal networks also mediate the pathophysiology of many CNS disorders. Stimulation therapies, including localized brain and vagus nerve stimulation, electroshock, and acupuncture, are proposed to activate "therapeutic" neuronal networks. These therapeutic networks are dormant prior to stimulatory treatments, but when the dormant networks are activated they compete with pathophysiological neuronal networks, disrupting their function. This competition diminishes the disease symptoms, providing effective therapy for otherwise intractable CNS disorders, including epilepsy, Parkinson's disease, chronic pain, and depression. Competition between stimulation-activated therapeutic networks and pathophysiological networks is a major mechanism mediating the therapeutic effects of stimulation. This network interaction is hypothesized to involve competition for "control" of brain regions that contain high proportions of conditional multireceptive (CMR) neurons. CMR regions, including brainstem reticular formation, amygdala, and cerebral cortex, have extensive connections to numerous brain areas, allowing these regions to participate potentially in many networks. The participation of CMR regions in any network is often variable, depending on the conditions affecting the organism, including vigilance states, drug treatment, and learning. This response variability of CMR neurons is due to the high incidence of excitatory postsynaptic potentials that are below threshold for triggering action potentials. These subthreshold responses can be brought to threshold by blocking inhibition or enhancing excitation via the paradigms used in stimulation therapies. Participation of CMR regions in a network is also strongly affected by pharmacological treatments (convulsant or anesthetic drugs) and stimulus parameters (strength and repetition rate). Many studies indicate that treatment of unanesthetized animals with antagonists (bicuculline or strychnine) of inhibitory neurotransmitter (GABA or glycine) receptors can cause CMR neurons to become consistently responsive to external inputs (e.g., peripheral nerve, sensory, or electrical stimuli in the brain) to which these neurons did not previously respond. Conversely, agents that enhance GABA-mediated inhibition (e.g., barbiturates and benzodiazepines) or antagonize glutamate-mediated excitation (e.g., ketamine) can cause CMR neurons to become unresponsive to inputs to which they responded previously. The responses of CMR neurons exhibit extensive short-term and long-term plasticity, which permits them to participate to a variable degree in many networks. Short-term plasticity subserves termination of disease symptoms, while long-term plasticity in CMR regions subserves symptom prevention. This network interaction hypothesis has value for future research in CNS disease mechanisms and also for identifying therapeutic targets in specific brain networks for more selective stimulation and pharmacological therapies.
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PMID:Electrical stimulation therapies for CNS disorders and pain are mediated by competition between different neuronal networks in the brain. 1876 89

During immuno-mediated attack of the brain, activation of endocannabinoids represents a protective mechanism, aimed at reducing both neurodegenerative and inflammatory damage through various and partially converging mechanisms that involve neuronal and immune cells. Here, we review the main alterations of the endocannabinoid system (ECS) within the central nervous system and in peripheral blood mononuclear cells, in order to discuss the intriguing observation that elements of the peripheral ECS mirror central dysfunctions of endocannabinoid signaling. As a consequence, elements of blood ECS might serve as novel, non-invasive diagnostic tools of several neurological disorders, and targeting the ECS might be useful for therapeutic purposes. In addition, we discuss the appealing working hypothesis that the presence of type-1 cannabinoid receptors on the luminal side, and that of type-2 cannabinoid receptors on the abluminal side of the blood-brain barrier, could drive a unidirectional transport of AEA in the luminal --> abluminal direction (i.e., from blood to brain), thus implying that blood may be a reservoir of AEA for the brain. On this basis, it can be expected that an unbalance of the endogenous tone of AEA in the blood may sustain a similar unbalance of its level within the brain, as demonstrated in Huntington's disease, Parkinson's disease, multiple sclerosis, attention-deficit/hyperactivity disorder, schizophrenia, depression and headache.
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PMID:The endocannabinoid system in peripheral lymphocytes as a mirror of neuroinflammatory diseases. 1878 87

Stem cells, as subjects of study for use in treating neurological diseases, are envisioned as a replacement for lost neurons and glia, a means of trophic support, a therapeutic vehicle, and, more recently, a tool for in vitro modeling to understand disease and to screen and personalize treatments. In this review we analyze the requirements of stem cell-based therapy for clinical translation, advances in stem cell research toward clinical application for neurological disorders, and different animal models used for analysis of these potential therapies. We focus on Parkinson's disease (typically defined by the progressive loss of dopaminergic nigral neurons), stroke (neurodegeneration associated with decreased blood perfusion in the brain), and multiple sclerosis (an autoimmune disorder that generates demyelination, axonal damage, astrocytic scarring, and neurodegeneration in the brain and spinal cord). We chose these disorders for their diversity and the number of people affected by them. An additional important consideration was the availability of multiple animal models in which to test stem cell applications for these diseases. We also discuss the relationship between the limited number of systematic stem cell studies performed in animals, in particular nonhuman primates and the delayed progress in advancing stem cell therapies to clinical success.
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PMID:Preclinical assessment of stem cell therapies for neurological diseases. 2007 96


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