ANOTHER CHANNEL OF HOPE ...
"
The vaccine approach utilizes a compound called Copaxone or Cop-1, a Food and Drug Administration (FDA)-approved and well-tolerated drug. Cop-1 has been used effectively in patients with chronic neuroinflammatory disease such as relapsing remitting multiple sclerosis for more than a decade. Given the safety record for Cop-1 and that current treatments for Parkinson's disease remain palliative, such a vaccination strategy represents a promising therapeutic avenue that can readily be used in human clinical trials, said Drs. Gendelman and Przedborski. "



Therapeutic vaccine approach for Parkinson's disease
Posted: Feb 7, 2008 04:52 PM

Updated: Feb 11, 2008 05:50 PM
http://www.nebraska.tv/Global/story.asp?S=7836721

by Karen Burbach, UNMC public affairs

Scientists at UNMC and Columbia University Medical Center in New York have discovered a new vaccine approach that successfully prevents the death of brain cells in a mouse model of Parkinson's disease.

The findings appear in the Proceedings of the National Academy of Sciences (PNAS) of the United States of America. PNAS is among the world's most-cited multidisciplinary scientific journals. The report, titled "Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson's disease," is now online. A print copy will be released June 22.

"It's a significant conceptual advance for Parkinson's disease therapy," said Howard Gendelman, M.D., David T. Purtilo Distinguished Chair of Pathology and Microbiology at UNMC and director of the Center for Neurovirology and Neurodegenerative Disorders (CNND) where the research was conducted. "As of today drugs are available which only treat symptoms of disease. Regrettably, nothing is now available that prevents or reverses the course of brain degeneration. Our vaccine approach changes this by bringing a new excitement to a developing field of investigation; called neuroprotective medicine. A vaccine therapy that protects the dopamine nerve cells damaged in Parkinson's disease is novel."
"The research is very exciting," said Serge Przedborski, M.D., Ph.D., professor of neurology and pathology in the Center for Neurobiology and Behavior at Columbia University and a world-renowned expert in Parkinson's disease research. "Using this approach, the harmful aspects of inflammation associated with Parkinson's disease could be eliminated."

Clinical trials to follow

The discovery, however, is just the beginning, Dr. Gendelman said. More research is being done at UNMC to improve this approach. Some aspects include finding the types of immune cells responsible for the protection as well as developing diagnostic techniques like enhanced magnetic resonance imaging to track disease progression. Clinical trials in humans are being developed at Columbia University.

"This will change how we treat neurodegenerative diseases," said Harris Gelbard, M.D., Ph.D., professor of neurology at the University of Rochester Medical Center. "It's a groundbreaking advance."

Kudos to CNND team

Dr. Gendelman credited Eric Benner, an M.D., Ph.D. student at UNMC, in playing a principal role in developing, then testing the Parkinson's vaccine approach over the past four years. "It was an incredible feat to integrate state-of-the-art animal research with similar advances in vaccine development," he said. "Eric simply did an outstanding job.

"Dr. R. Lee Mosley provided invaluable help to Eric and other CNND scientists both in vaccine strategies and in measuring immune responses. We were blessed with outstanding scientists all working together for a common purpose. We couldn't have assembled a better team."

Containing a destructive process

The CNND has based much of its research on the premise that activation of two types of support cells in the brain - microglia and astrocytes - mediate inflammatory events that contribute to the death of neurons, the nerve cells in the nervous system that receive and send out electrical signals.

"The destruction of neurons in this way is well known to lead to the development of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and HIV-1-associated dementia," Benner said. "The vaccine approach can affect the inflammatory brain response and at the same time increase the local expression of neurotrophins or nerve cell growth promoting factors in the brain."

"What we have done is take an evil process (inflammation) and turned it on its heels," Dr. Gendelman said. "We've taken a destructive process and contained it."

Role of secondary inflammatory responses

Secondary inflammatory responses underlie how brain damage occurs in many human neurodegenerative disorders. This was the premise in which the CNND was built and is sustained from pivotal work done by Dr. Gendelman and his collaborators in HIV-associated dementia.

Drs. Gendelman and Przedborski and Benner emphasized that although the vaccine protects mice against the type of cell death observed in Parkinson's disease, there is no guarantee it will act the same way in humans. Clinical trials ultimately will determine if the observations seen in mice can be translated and prove useful in humans with disease.

Vaccine shows promise in mice

In mice, however, the concept has shown great promise, preventing the progression of the disease. In their research, CNND scientists injected an immunogen that cross reacts with myelin basic protein into mice with an experimental form of Parkinson's disease. "The mice mounted an immune response that affected inflammatory responses in the brain and the production of neurotrophic, or neuronal growth factors," Benner said.

The immune cells can go into brain regions that are affected during disease and reducee the inflammation in the area of injury, as it would elsewhere in the body following local infections and trauma. This may be a way to use the body's own defense to work towards its own repair. Importantly such protective strategies eliminate the need to use more controversial approaches for brain repair including the use of embryonic stem cells and fetal cells. Unlike fetal or stem cells, this vaccine therapy relies on harnessing the body's own immune system. It's a very novel means for combating neurological diseases." More on Parkinson's disease

Parkinson's disease is a chronic, debilitating disease without a cure. There also is no preventive or restorative treatment available. In the United States, at least 500,000 people are believed to suffer from Parkinson's disease, and about 50,000 new cases are reported annually. The incidence is expected to increase as the average age of the population increases. The disorder appears to be slightly more common in men than women.

Vaccine is FDA-approved

The vaccine approach utilizes a compound called Copaxone or Cop-1, a Food and Drug Administration (FDA)-approved and well-tolerated drug. Cop-1 has been used effectively in patients with chronic neuroinflammatory disease such as relapsing remitting multiple sclerosis for more than a decade. Given the safety record for Cop-1 and that current treatments for Parkinson's disease remain palliative, such a vaccination strategy represents a promising therapeutic avenue that can readily be used in human clinical trials, said Drs. Gendelman and Przedborski.

Benner studied the mouse model of Parkinson's disease in Dr. Przedborski's laboratory and transferred it to Dr. Gendelman's laboratory in Nebraska. The discovery of Cop-1 was made at the Weizmann Institute nearly three decades ago.

Team approach

Benner, who performed the vaccine studies under the mentorship of Dr. Gendelman, is credited with the advance, along with other CNND and Columbia scientists including, but not only, R. Lee Mosley, Ph.D., an expert immunologist and vaccine specialist at UNMC; Travis B. Lewis, a technician and current M.D., Ph.D., student at the University of Alabama at Birmingham; and Vernice Jackson-Lewis, Ph.D., a well-respected and accomplished neuroscientist at Columbia.

Generous support makes research possible

The work was supported in part, by the National Institutes of Neurological Disorders and Stroke, the U.S. Department of Defense, the Alan and Marcia Baer Foundation, the Francis and Louis Blumkin Foundation, Inc., the Terry K. Watanabe Charitable Trust, the Seline Family Foundation, the Lowenstein Foundation, the Lillian Goldman Charitable Trust, the Parkinson's Disease Foundation and the MDA/Wings-Over-Wall Street.

The CNND's novel research in this area was made possible by financial support from several individuals in the Omaha community, Dr. Gendelman said. "Their generous support allows us to be world leaders in a new and dynamic field of investigation," he said. "It also gives new hope to people with Parkinson's disease."


http://app1.unmc.edu/publicaffairs/t...cfm?match=2648

The drug is used in multiple sclerosis, an autoimmune disease. Perhaps PD is an autoimmune disease afterall.

Trends in Molecular Medicine
Volume 8, Issue 7, 1 July 2002, Pages 319-323

Opinion

Dual action of glatiramer acetate (Cop-1) in the treatment of CNS autoimmune and neurodegenerative disorders

Jonathan Kipnis and Michal SchwartzE-mail The Corresponding Author
Dept of Neurobiology, The Weizmann Institute of Science, 76100, Rehovot, Israel

Available online 4 July 2002.

Abstract

Protective autoimmunity is the body's defense mechanism against destructive self-compounds such as those commonly associated with neurodegenerative disorders. Autoimmune disease and neurodegenerative disorders can thus be viewed as two extreme manifestations of the same process. Therefore, when designing therapy, it is important to avoid an approach that will cure the one by invoking the other.

One way to stop, or at least slow down, the progression of neurodegeneration without risking development of an autoimmune disease is by boosting protective autoimmunity in a well-controlled way. Copolymer 1 (Cop-1), an approved drug for the treatment of multiple sclerosis, can be used as a treatment for autoimmune diseases and as a therapeutic vaccine for neurodegenerative diseases.

We propose that the protective effect of Cop-1 vaccination is obtained through a well-controlled inflammatory reaction, and that the activity of Cop-1 in driving this reaction derives from its ability to serve as a ‘universal antigen’ by weakly activating a wide spectrum of self-reactive T cells.

http://www.sciencedirect.com/science...c61589c6f21d1f

• Autoimmune neuroprotection – a physiological self-repair mechanism


Neurodegenerative disorders are commonly associated with ongoing neuronal loss in the central nervous system (CNS) [1 and 2]. Following the loss of neurons caused by primary risk factors, additional (‘secondary’) neuronal loss is mediated by self-compounds, such as glutamate, nitric oxide or reactive oxygen species, that exceed their physiological concentrations. These compounds are implicated in various types of neurological disorders and acute CNS injuries [3, 4, 5, 6 and 7]. It is interesting to note that destructive components common to neurodegenerative diseases have also been identified in autoimmune diseases such as multiple sclerosis (MS); in this disease, myelin damage in the CNS is accompanied by subsequent neuronal loss [8, 9, 10 and 11].

Immune activity in the CNS has long been considered detrimental, and patients with neurodegenerative disorders and acute injuries are therefore commonly treated with immunosuppressive drugs [12, 13, 14, 15, 16 and 17]. This negative view of inflammation derives largely from the fact that the presence of immune cells in the brain has been reported mainly in pathological situations. Indeed, these cells came to be regarded as the cause of the pathology, not as the result, and certainly not as cells recruited for the purpose of physiological repair.

Thus, for example, the immune components (e.g. activated microglia, blood-borne macrophages, CD8+ and CD4+ T cells) found in damaged regions and plaques in patients with neurodegenerative syndromes were assumed to be causatively associated with the syndrome [18 and 19]. However, studies in the past few years have shown that immune cells, in particular autoimmune T cells, play an essential role in protecting the injured CNS from the ongoing spread of damage [20, 21, 22, 23, 24 and 25].

Moreover, it has proved possible to boost protective immunity in rats and mice without risk of inducing neurodegenerative disease, as will be discussed here.
Autoimmune neuroprotection – a physiological self-repair mechanism

In certain strains of rats, passive transfer of autoimmune T cells reactive to myelin-related self-antigens induces a transient autoimmune syndrome known as experimental autoimmune encephalomyelitis (EAE) [26 and 27]. If these strains of rats are subjected either to partial crush injury of the optic nerve or to contusive injury of the spinal cord, the autoimmune cell transfer not only induces EAE but also confers neuroprotection by reducing secondary degeneration of the damaged neural tissue [21 and 23]. Recent studies have provided persuasive evidence that the observed autoimmune neuroprotection is not merely the outcome of an experimental manipulation, but is a physiological response evoked systemically by the CNS injury [20 and 28]. Furthermore, in several strains of mice and rats, an absence of mature T cells (e.g. in nude mice or in rats subjected to thymectomy at birth) results in a worse outcome from CNS injury than in their wild-type counterparts [20 and 28].

The way in which autoimmune T cells prevent the degenerative consequences of CNS insults or protect the injured nerve from self-destructive mediators of toxicity is currently under intensive investigation. Studies have shown that active autoimmune T cells engage in a dialogue with CNS-resident microglia or with infiltrating macrophages [29]. Among the effects attributed to such dialogue is activation, through MHC class II interaction, of the affected cells, enabling them to clear the injury site of potentially harmful factors, such as destructive self-compounds.

On the basis of the ability of activated T cells and monocytes to produce neurotrophic factors, it was further suggested [30 and 31] that macrophages might serve as a source of neurotrophins. Thus, T cells might participate in the activation of macrophages, through MHC class II interaction, for the production of such factors. However, it was recently shown that the autoimmune T cells are not the only T cells participating in autoimmune neuroprotection, but that another population of CD4+ T cells (probably of a regulatory phenotype) is also an essential participant (J. Kipnis et al., unpublished).

The phenotype of the T cells that regulate neuroprotection is still unknown. The most promising candidates are naturally occurring CD4+CD25+ regulatory T cells, which are antigen specific, and natural killer cells, which play an important role in terminating EAE [32]. In view of the results described above, it is reasonable to suggest that nonspecific therapeutic suppression of the immune response to CNS trauma (e.g. by depriving the body of proinflammatory cytokines) might be harmful for neurons in the long term. This might be the case even though the immune involvement appears to be at some cost in terms of neuronal loss to the tissue, since the benefit of neuroprotection afforded by the ongoing immune activity, if well controlled, will eventually outweigh the cost. It therefore seems that a preferable therapy would be antigen-specific immunomodulation aimed at boosting and regulating the inflammatory response [33 and 34] to a CNS insult [24].

It was recently discovered that it is possible to boost protective immunity in rats and mice without the risk of inducing EAE, by vaccinating the injured animal with glatiramer acetate (Cop-1) [35], a drug used clinically to alleviate the symptoms of MS.

Vaccination with Cop-1 emulsified in a strong adjuvant reduced glutamate-mediated cytotoxicity in the rodent retinal ganglion cell (RGC) model and attenuated the symptoms of a chronic neurodegenerative disorder (simulating glaucoma) in a rat model of high intraocular pressure [35 and 36]. The following sections discuss the dual effects of Cop-1 in protecting against ‘destructive’ autoimmunity (seen in patients with autoimmune diseases such as MS) and in inducing or boosting ‘protective’ autoimmunity, thereby promoting neuronal survival in cases of neurodegenerative disorders.

Low-affinity self-reacting Tcells are activated by Cop-1: a ‘safe’ therapeutic vaccine for neurodegenerative disorders

An initial assumption was that Cop-1, by crossreacting with MBP or other components of myelin, might enable Cop-1-specific T cells to recognize the damaged tissue, accumulate there, and undergo activation resulting in neuroprotection [35]. However, more-recent studies have shown that T cells reactive to Cop-1 do not proliferate when exposed to myelin proteins [48]. After partial crush injury of the rat optic nerve, myelin epitopes are exposed at the site of injury. Following injury, peripheral lymphocytes, regardless of their antigenic specificity, enter the CNS [49].

T cells reactive to myelin proteins are activated at the site of injury or in the cervical lymph nodes, where the drainage of CNS antigens probably takes place [50 and 51]. Recent studies have shown that activation of autoimmune T cells after injury is a prerequisite for neuroprotection, and that such activation can be boosted by immunization with self-antigens (in this case myelin proteins) [21, 22 and 52]. These findings led us to suggest that, upon passive transfer of Cop-1-specific T cells or active immunization with Cop-1, T cells arriving at the site of injury will serve a dual role: first they will trigger proinflammatory activity and later they will terminate their own activation [35].

Indeed, examination of this possibility showed not only that Cop-1-reactive T cells accumulate in the normal (undamaged) optic nerve, where only myelin-specific T cells can accumulate, but also that their numbers are smaller than those of the accumulated myelin-specific T cells [35]. These findings pointed to crossreactivity of Cop-1-activated T cells with myelin proteins in vivo.

Activated Cop-1-reactive T cells produce neurotrophic factors, but their pattern of neurotrophin expression might differ from that of MBP-reactive activated T cells [35]. Accordingly, it was suggested that Cop-1-reactive T cells, after arriving at the site of the injury, are weakly reactivated by self-antigens residing at the lesion site. Such reactivated T cells were shown to produce cytokines associated with both Th1 (interferon γ) and Th2 (interleukin 4) [35], indicating that Cop-1-reactive T cells are potentially capable of self-regulation.

We suggest that the reactivated proinflammatory Cop-1-reactive T cells in turn activate the resident microglia (as suggested above), enabling them to clear the lesion site of toxic self-compounds and to display enhanced phagocytic activity for nonspecific clearance. In addition, these T cells might activate microglia to produce neurotrophic factors.

According to the above scenario, passive transfer of activated Cop-1-reactive T cells leads to their accumulation at the site of injury, where they reinforce the local immune response (inflammation) at the injury site. However, this interpretation of activity as an outcome of crossreactivity with MBP has turned out to be an oversimplification: Cop-1-activated T cells were also found to be neuroprotective in other models of CNS injury, where myelin-associated antigens are not active, such as the insult caused by direct exposure of RGCs to glutamate toxicity or the death of RGCs resulting from increased intraocular pressure in a model of high-tension glaucoma [36].

The question then arises: how can Cop-1 vaccine be effective under conditions where myelin-related vaccines are not? These results point to the possibility of crossreactivity between Cop-1-reactive T cells and other self-proteins.

Cop-1 cross-recognizes T cells reactive to various antigens, and it might bind MHC class II molecules without being processed [53]. It is possible that Cop-1 acts as a universal antigen, as suggested by Hafler [44]. Furthermore, vaccination with Cop-1 activates different T-cell clones with a wide range of antigenic specificities [54 and 55] and some of these clones might weakly crossreact with epitopes of myelin antigens, boosting the endogenous response to white matter injury; by contrast, others might weakly crossreact with retinal-exclusive peptides (or with self-antigens in other tissues), inducing a protective immune response in the retina when protection of RGCs from glutamate toxicity is required. We suggest that T cells reactive to Cop-1 should be referred to not as Cop-1-specific T cells, but as low-affinity self-reactive T cells activated by Cop-1.

According to this view, Cop-1, being a weak self-reactive antigen, will weakly activate numerous self-reactive T cells. These T cells will therefore slowly undergo proliferation, which will be balanced to some extent by the proliferation of regulatory T cells also activated by Cop-1. Since the rate of proliferation of the regulatory clones (e.g. naturally occurring CD4+CD25+ regulatory T cells) is slower than that of the effector (self-reactive) T cells [56], there is a period of time in which effector Th1 cells can act without being suppressed by regulatory T cells ( Fig. 1).

This scenario is in line with our recent suggestion that a pro-inflammatory immune activity is a prerequisite for neuroprotection, but that it must be stopped on time (J. Kipnis et al., unpublished)......

.....It is important to bear in mind that MS is now recognized not only as a disorder related to myelin, but also as a neuronal disorder [62, 63 and 64]. Glutamate, a principal mediator of toxicity in neurodegenerative disorders, has also been identified in patients with MS [62 and 63]. Protection against the harmful effect of glutamate can be obtained by vaccination with Cop-1 [36]. Giving Cop-1 to patients with MS using the same regimen as for patients with neurodegenerative disorders might therefore be worth considering.

Concluding remarks

We suggest that the optimal application of Cop-1 for the treatment of neurodegenerative diseases is by vaccination in order to activate the weakly self-reactive Th1 cells in a well-regulated way. According to our perception of autoimmunity, the regimen for Cop-1 administration in individuals with autoimmune disease (daily injection) differs from that required for treatment after CNS injury. Future studies should be aimed at establishing the optimal regimen for Cop-1 administration in individuals with diseases that are both autoimmune and neurodegenerative, to achieve both neuroprotection (against degeneration) and arrest of the demyelination process (i.e. prevention of disease).

Elucidation of the precise mechanism underlying the interaction of Cop-1-reactive T cells with self-antigens might shed light on the Cop-1-mediated protective mechanisms, which are so similar and yet so different, in autoimmune diseases and in neurodegenerative disorders.

http://www.sciencedirect.com/science...c61589c6f21d1f

Quantitative 1H Magnetic Resonance Spectroscopic Imaging Determines Therapeutic Immunization Efficacy in an Animal Model of Parkinson's Disease

Michael D. Boska,1,2 Travis B. Lewis,1

The Journal of Neuroscience, February 16, 2005, 25(7):1691-1700;

Nigrostriatal degeneration, the pathological hallmark of Parkinson's disease (PD), is mirrored by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. MPTP-treated animals show the common behavioral, motor, and pathological features of human disease.

We demonstrated previously that adoptive transfer of Copaxone (Cop-1) immune cells protected the nigrostriatal dopaminergic pathway in MPTP-intoxicated mice. Herein, we evaluated this protection by quantitative proton magnetic resonance spectroscopic imaging (1H MRSI). 1H MRSI performed in MPTP-treated mice demonstrated that N-acetyl aspartate (NAA) was significantly diminished in the substantia nigra pars compacta (SNpc) and striatum, regions most affected in human disease.

When the same regions were coregistered with immunohistochemical stains for tyrosine hydroxylase, numbers of neuronal bodies and termini were similarly diminished.

MPTP-intoxicated animals that received Cop-1 immune cells showed NAA levels, in the SNpc and striatum, nearly equivalent to PBS-treated animals.

Moreover, adoptive transfer of immune cells from ovalbumin-immunized to MPTP-treated mice failed to alter NAA levels or protect dopaminergic neurons and their projections.

These results demonstrate that 1H MRSI can evaluate dopaminergic degeneration and its protection by Cop-1 immunization strategies. Most importantly, the results provide a monitoring system to assess therapeutic outcomes for PD.

INTRO:


Parkinson's disease (PD) is a common and debilitating neurodegenerative disorder. Symptoms of tremor, rigidity, bradykinesia, and postural instability commonly progress to significant movement and cognitive dysfunction. Pathological changes in the substantia nigra pars compacta (SNpc) and striatum consist of nigral dopaminergic neuronal loss, intraneuronal cytoplasmic inclusions or "Lewy Bodies," gliosis, and striatal dopamine depletion (Lang and Lozano, 1998Go; Braak and Braak, 2000Go; Fahn and Przedborski, 2000Go). Innate immunity involving resident microglial cells with secretion of neurotoxic cytokines and production of reactive oxygen and nitrogen species can contribute to nigrostriatal dopaminergic degeneration (Gao et al., 2003Go).

Behavioral and neuropathological outcomes of human disease are mirrored in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated animals (Wu et al., 2003Go). Such animals demonstrate degeneration of the nigrostriatal system characterized by diminished dopamine, neuronal and termini loss (Tanji et al., 1999Go; Bezard et al., 2001Go), and glial inflammation (Gao et al., 2003Go). For the latter, attenuating brain inflammation can affect the disease process (He et al., 2001Go). In a recent report from our laboratories, immune cells recovered from Copaxone (Cop-1; glatiramer acetate)-vaccinated animals and injected into MPTP-treated animals entering inflamed brain regions, increased expression of astrocyte glial cell line-derived neurotrophic factor (GDNF), and attenuated microglial responses. These effects parallel protection of the nigrostriatal pathways (Benner et al., 2004Go). Importantly, both microglial deactivation and GDNF administration into the caudate and putamen show potential clinical benefit (Gill et al., 2003Go; Kirik et al., 2004Go). Cop-1 immunization generates nonencephalitic T cells that cross react with myelin basic protein, elicits few side effects (Johnson, 1996Go; Teitelbaum et al., 1997Go; Aharoni et al., 1999Go; Chen et al., 2001Go), and shows efficacy for relapsing-remitting multiple sclerosis (Johnson, 1996Go; Chen et al., 2001Go). The ability of Cop-1 to affect immune system responses in animal models of neurodegenerative disorders supports its potential for human use (Angelov et al., 2003Go; Benner et al., 2004Go; Kipnis et al., 2004b).

Clinical responses may be limited by the timing of therapeutic intervention. Currently, PD is commonly diagnosed when >50% of SNpc neurons and their terminals are destroyed (Bernheimer et al., 1973Go). An early diagnosis would enable early treatment intervention at times when positive outcomes are likely. In this regard, functional imaging, including single-photon emission computerized tomography (SPECT) (Seibyl et al., 1995Go; Benamer et al., 2000Go), positron emission tomography (PET) (Vingerhoets et al., 1994Go; Eidelberg et al., 1995aGo,bGo; Morrish et al., 1996Go), proton magnetic resonance spectroscopic imaging (1H MRSI) (Cruz et al., 1997Go; Tedeschi et al., 1997Go), and functional magnetic resonance imaging (MRI) (Ceballos-Baumann, 2003Go), are promising approaches for early PD diagnosis. The potential for detection of early disease stage is significant (Burn and O'Brien, 2003Go; Simpkins and Jankovic, 2003Go).

With this in mind, we developed high-spatial resolution 1H MRSI to monitor PD-affected brain subregions, the SNpc and striatum. Analysis demonstrated that N-acetyl aspartate (NAA) was reduced in the SNpc of MPTP mice. Significantly higher [NAA] was seen in MPTP mice that received Cop-1 immune cell-adoptive transfers than in MPTP or MPTP/ovalbumin (OVA) animals. We demonstrate that [NAA] can assess nigrostriatal degeneration and therapeutic responses for MPTP intoxication.

http://www.jneurosci.org/cgi/content/full/25/7/1691

DISCUSSION:

PD is characterized by slow and progressive degeneration of the nigrostriatal dopaminergic pathway (Lang and Lozano, 1998Go; Langston et al., 1999Go; Dawson and Dawson, 2003Go). Currently, approved treatment modalities for PD remain only palliative (Shults, 2003Go). We previously demonstrated that attenuation of microglial responses and adoptive transfer of Cop-1-specific immune cells into MPTP-treated animals can achieve glial expression of GDNF. Such responses parallel the protection of dopaminergic neurons and their striatal projections in Cop-1/MPTP mice (Benner et al., 2004Go).

No laboratory tests for PD currently exist. Thus, history and neurological examination remain the principal diagnostic methods. Disease manifests only after significant damage, typically >50% neuronal loss, occurs to the SNpc (Bernheimer et al., 1973Go). Most commonly, symptoms begin insidiously and consist of bradykinesia and resting tremor and progress to immobility and balance difficulties. Disease manifestations in patients over the age of 65 are misdiagnosed as arthritis, depression, and global weakness (Wolters, 2000Go, 2001Go; Garber and Friedman, 2003Go). Behavioral and mental disorders, including dementia, can occur together with motor dysfunction, but cognitive deficits usually occur only late in the course of disease (Locascio et al., 2003Go). Levels of fluoro-L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine transporters are used to assess L-DOPA uptake and dopaminergic nerve terminals through PET or SPECT analyses, respectively (Vingerhoets et al., 1994Go; Eidelberg et al., 1995aGo,bGo; Seibyl et al., 1995Go; Morrish et al., 1996Go; Benamer et al., 2000Go); however, both require substantial neural damage to register significant discrimination from normal and attain diagnostic sensitivity. Thus, together, a definitive diagnosis of PD requires substantive clinical manifestations (DeKosky and Marek, 2003Go).

In our current study, we used high-field 1H MRSI with histological coregistration to measure, in a sensitive and specific manner, nigrostriatal dopaminergic degeneration. Such measurements allowed quantitative analysis of neuroprotective events that follow adoptive transfer of Cop-1 immune cells. Previous studies using single-voxel 1H MRSI showed reduced NAA/Cho ratios in the SN and thalamus of PD patients that were reversed after successful stereotactic thalamotomy, a procedure used to control symptoms in medically intractable PD (Baik et al., 2003Go). MRSI analysis of the striatum has yielded inconsistent results. One study demonstrated increased [Cho] in the striatum for which the biological significance is not clear (Clarke and Lowry, 2001Go) but may be reflective of inflammatory responses in PD patients. 1H MRS in MPTP-intoxicated cats demonstrated reduced striatal [NAA] (Podell et al., 2003Go); however, the degree of feline MPTP intoxication was pathologically more severe than induced in our study. Our data demonstrate that 1H MRSI and specifically [NAA] reflect dopaminergic loss in MPTP-intoxicated mice and can be used to monitor putative neuroprotective therapies.

Previous work from our laboratory and from others demonstrate that adaptive immune responses provide neuroprotection against secondary damage after a variety of neural insults, including MPTP intoxication (Benner et al., 2004Go), traumatic injury of motor neurons and optic nerve (Moalem et al., 1999Go; Kipnis et al., 2000Go; Angelov et al., 2003Go), the superoxide dismutase 1 mutation causing amyotrophic lateral sclerosis (ALS) (Angelov et al., 2003Go), retinal ganglion toxicity by glutamate (Schori et al., 2001Go), and neurotransmitter imbalance by dizocilpine maleate and amphetamines (Kipnis et al., 2004Go). Cop-1 induces autoimmune T-cells preventing additional degeneration of the CNS after initial damage. The mechanisms of Cop-1 neuroprotection, including an analysis of the T-cell subtypes involved in the neuroregulatory responses, remain under investigation (Kipnis and Schwartz, 2002Go).

More specifically, we previously showed protection against MPP+ degeneration of dopaminergic neurons. In that study, the sparing of neuronal and their terminal connections to the striatum was accompanied by increased levels of astrocyte-generated GDNF and interleukin-10 (Benner et al., 2004Go). It is, nonetheless, likely that COP-1-induced regulatory T-cells affect a number of neuroimmune activities. The balance between proinflammatory and anti-inflammatory cytokines, together with induction of neurotrophins and other growth factors, is likely operative. Direct correlation of in vivo changes obtained using quantitative 1H MRSI and quantitative assessment of tissue immunomodulatory factors may, in subsequent works, reveal detailed mechanisms for these neuroprotective processes.

Quantitative MRS is a technique that can be prone to error. The primary source of error is the relaxation (T1 and T2) corrections of the signal amplitudes, because these parameters are difficult to measure and can change in pathological conditions. The degree to which this will contribute to potential error increases with decreased repetition time and increased echo time. In addition to difficulties with relaxation properties, difficulties can exist in accurately measuring metabolites near the water resonance because of incomplete water suppression or residual stimulated echoes. For these reasons, we selected acquisition parameters that minimize T1 and T2 relaxation corrections (TE, 33 ms; TR, 4 s) and only reported results from metabolites that have long T2 and are well removed from the spectral regions of residual water and occasional stimulated echoes (NAA, Cre, Cho). Developments have been implemented during the acquisition of these data (Smallcombe et al., 1995Go) to eliminate residual stimulated echoes to allow for reliable quantitation of a broader array of metabolites in future studies.

As a metabolite found primarily within neurons, measures of NAA are used often as a noninvasive surrogate marker of neuronal integrity for a wide range of neurodegenerative disorders, including stroke, multiple sclerosis, ALS, AD, and human immunodeficiency virus 1-associated dementia (Swindells et al., 1995Go; Chen et al., 2000Go; Suhy et al., 2002Go; Tedeschi et al., 2002Go; Chung et al., 2003Go; Schuff et al., 2003Go). Its use as a diagnostic test for PD has been hampered by the inability of previous tests to precisely localize it to the SNpc, a necessary prerequisite because of the exacting relationship of NAA to neuronal injury and the requirement for high-field MRSI to ensure precise quantitative measurements (Clarke et al., 1997Go; Cruz et al., 1997Go; Federico et al., 1997Go; Brooks, 2000Go; Clarke and Lowry, 2000Go; Firbank et al., 2002Go; Baik et al., 2003Go). Nevertheless, a number of advantages to NAA measurements are evident, including its exclusive relationship to synthesis in neuronal mitochondria and reduction in mitochondrial dysfunction (Clark, 1998Go; Signoretti et al., 2001Go). Such subcellular injury may also be responsible for [NAA] reductions that we observed in and around the SNpc of MPTP-intoxicated animals, which may reflect partial volume effects associated with glutaminergic and GABAergic neurons, especially with HPLC measures of [NAA].

MPTP acts by glial cell conversion to the active neurotoxin, MPP+, which is preferentially taken up by dopaminergic neurons, binds complex I of the mitochondrial electron transport chain of those neurons, and primarily affects the dopaminergic neurons of the SNpc (Jackson-Lewis et al., 1995Go; Przedborski et al., 2001Go; Crocker et al., 2003Go). Because the neurotoxin is reported to have minimal effects on GABAergic neurons (Irwin and Langston, 1985Go; Javitch et al., 1985Go; Buck and Amara, 1994Go; Santiago et al., 1996Go; Bezard et al., 1999Go), we posit that the [NAA] loss in the regions surrounding the SN could reflect glial inflammatory products inducing more widespread changes in neuronal metabolism. Clearly, microglial activation and its subsequent secretory neurotoxic activities have been shown to be an important source of secondary neuronal damage in both the MPTP model and in human PD as well as many other neurodegenerative disorders (McGeer et al., 1988Go; McGeer and McGeer, 1998Go; Hunot et al., 1999Go; Wu et al., 2003Go) and may affect, in part, mitochondrial function with resulting perturbation of [NAA]. In support of the correlation of migroglial activation and neurodegeneration, postmortem examination of PD patients shows nigrostriatal degeneration associated with significant levels of reactive human leukocyte antigen-DR-positive microglial cells in the SN and is also commonly found in stroke, Alzheimer's disease, and amyotrophic lateral sclerosis (McGeer and McGeer, 1998Go) Increases in brain cytokine levels are found in the brains and CSF of PD patients (Nagatsu et al., 2000Go). Microglia produce a plethora of toxic products including proinflammatory cytokines, oxygen-free radicals, quinolinic acid, glutamate, nitric oxide, and others. Oxidative stress and excitotoxicity brought on by activated microglia can by itself lead to nigrostriatal degeneration by activating receptors that contain intracytoplasmic death domains leading to apoptosis (Mochizuki et al., 1996Go; Anglade et al., 1997Go; Jenner and Olanow, 1998Go; Tatton et al., 1998Go; Olanow and Tatton, 1999Go). Moreover, in the MPTP model, the degenerative process is perpetuated by a mixture of direct MPP+-induced damage and microglial toxic activities (Herrera et al., 2000Go).

Anti-inflammatory drugs such as pioglitazone, a peroxisome proliferator-activated receptor-{gamma} agonist, and the tetracycline derivative minocycline can reduce microglial responses and protect dopaminergic neurons in MPTP animals (Du et al., 2001Go; He et al., 2001Go; Breidert et al., 2002Go; Wu et al., 2002Go). Vaccination can also attenuate neuronal injury by affecting microglial responses (Moalem et al., 1999Go; Hammarberg et al., 2000Go; Hauben et al., 2000Go; Fisher et al., 2001Go). This approach may have wide applicability and effectiveness as shown in animal model systems, including neural trauma, glaucoma, ALS, AD, and PD (Krieger et al., 1976Go; Charness et al., 1989Go; Janus et al., 2000Go; Fisher et al., 2001Go; Hauben et al., 2001Go, 2003Go; Lemere et al., 2001Go; Weiner and Selkoe, 2002Go; Bakalash et al., 2003Go).

An unexpected observation made was the degree of [NAA] reduction seen in the SNpc indicated that secondary damage can occur to surrounding glutaminergic and GABAergic neurons (Calon et al., 1999Go, 2001Go). TH+ dopaminergic neurons occupy only 10-30% of total neurons in the 1H MRSI voxel containing the SNpc. However, [NAA] reduction in glutaminergic and GABAergic neurons does not appear causal for neuronal cell death as evidenced by the retention of Nissl+ neuronal counts in all treatment groups. [NAA] loss likely reflects mitochondrial dysfunction that should be reversible.

All together, whether severely affected dopaminergic neurons can be protected from the ravages of PD-associated neurodegeneration using therapeutic strategies outlined in this study is not yet known. However, the data outlined in this report and by others support the idea that such a goal is achievable. Neuroprotective strategies, such as the stereotactic infusion of GDNF, have entered clinical trials and shown benefit as treatments for PD (Gill et al., 2003Go; Kordower, 2003Go; Kirik et al., 2004Go). Having the means available to monitor therapeutic outcomes, such as those described here, will likely prove to be a significant forward step in realizing preventative and regenerative therapeutic goals for PD.

http://www.jneurosci.org/cgi/content...25/7/1691#SEC4

Medical Hypotheses
Volume 69, Issue 6, 2007, Pages 1219-1221

Glatiramer acetate could be a potential therapeutic agent for Parkinson’s disease through its neuroprotective and anti-inflammatory effects

Shih-Jen Tsai
doi:10.1016/j.mehy.2007.04.014

Summary

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. The hallmark pathologic feature of PD is dopamine deficiency, caused by the degeneration of nigrostriatal dopaminergic neurons. Current treatments for PD mainly address the dopaminergic features of the disease; however they do not modify the progression of neurodegeneration. The need for newer and more effective agents is consequently receiving a great deal of attention.

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, can promote survival of injured dopaminergic nigrostriatal neurons in the rodent. Postmortem studies have suggested that BDNF deficiency may play a role in PD pathogenesis. This is further supported by the finding that BDNF administration has a therapeutic effect in animal models of PD.

Glatiramer acetate (GA) is a collection of synthetic polypeptides approved for the treatment of relapsing–remitting multiple sclerosis. Preclinical studies have demonstrated that peripheral GA administration can enhance central BDNF activity and augment neurogenesis. Furthermore, PD has been associated with an inflammatory process in the brain.

Animal studies have demonstrated that GA administration has a central anti-inflammatory effect through the release of anti-inflammatory cytokines. From the above evidence, GA could act as a potential therapeutic agent for PD by increasing central BDNF and by exerting an anti-inflammatory effect. With the recent finding that GA administration can prevent neuronal loss and cognitive decline in Alzheimer’s disease double-transgenic mice, early GA treatment may also prevent neurodegeneration and manifestations of PD symptoms in subjects with familial Parkinson’s disease.


http://www.sciencedirect.com/science...178d7717a28dc2

Thank you Zflower for digging out related research . It points out to the fact that much of the research is done for academic promotion and often forgotten and not translated to practical use
The articles you post are several years old while the article I posted claims to break new ground !!!!!!!!!!!!!!!!!!!!!??????????????????