Interestingly, minocycline is effective with oral administration despite its limited penetration of the blood-brain-barrier. It has also been reported that minocycline reduces infarct size and microglial activation following both focal and global ischemia Yrjanheikki et al. Moreover, minocycline exhibits neuroprotective activity in models of Huntington's disease Chen et al. Neurosurgery, , P38 has also been implicated in Alzheimer's disease.
Recent analyses of postmortem brain tissues from individuals at different stages of disease progression have shown high levels of phosphorylated p38 in neuronal populations at early stages of the disease, particularly in the CA2 and CA1 regions of the hippocampus Sun et al. These data suggest that p38 may be involved in the early stages of cellular degeneration in Alzheimer's disease. Additionally, the expression of phosphorylated p38 is increased in astrocyte-like cells in the core and penumbra regions of an infarct following focal ischemia, and in the hippocampus following global forebrain ischemia.
Further, there is an increase in phosphorylated p38 in retinal ganglion cells undergoing cell death following axotomy of the optic nerve, and retinal ganglion cell death is reduced by the p38 inhibitor SB P38 has also been implicated in ntiric oxide NO induced neuronal death, and SB inhibits NO toxicity in primary neurons.
Although the etiology of chronic neurodegenerative diseases such as multiple sclerosis and Guillain-Barre syndrome are unknown, it is clear that they involve inflammatory and autoimmune components. Inflammatory responses are also involved in acute neurological disorders such as stroke and brain trauma, and p38 has been shown to regulate the expression of nitric oxide synthase, a molecule that plays a critical role in the excitotoxic death associated with stroke and traumatic injury.
The immunosuppressive and anti- inflammatory agents presently used to treat these disorders have met with limited success.
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What is needed, therefore, are compositions and methods for ameliorating deleterious aspects of a neuroinflammatory responses and the cell dysfunction and death that follows. It is a further object of the present invention to provide JNK and p38 inhibitors that serve a dual role in the treatment of chronic neuroinflammatory diseases such as MS and Guillain-Barre syndrome, and acute neuroinflammatory disorders such as stroke and nervous system trauma, by inhibiting autoimmune and inflammatory process while providing a direct neuroprotective effect.
Transplantation and references cited therein. Manolios et al. References describing methods for designing compounds by computer using structure activity relationships include Grassy et al. Protein Engineering 11 : ; Ashton et al. Drug Discovery Today 1 ; and Iyer et al. Also disclosed herein are methods using such RDP compositions to modulate biochemical signals signal transduction and the cellular and physiological processes impacted thereby. The RDP compositions disclosed herein also include compositions that are capable of modulating p38 activity, preferably kinase activity as directed at a substrate of p P38 and p38MAPK and grammatical equivalents are used interchangeably throughout the present disclosure.
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In a preferred embodiment provided herein are RDP compositions having a combination of two or more such activities. In one embodiment, the cell is a neuron. In another embodiment, the cell is a glial cell. In a third embodiment, the method is for reducing neuronal and glial cell death. In a third embodiment , the method is for reducing neuronal and glial cell apoptosis.
More than one agent may be used in combination with an RDP composition i. Preferred second agents include growth factors and cells, including oligodendrocytes and precursors thereof, glial cells that support oligondendrocytes, a variety of neuronal subtypes including dopaminergic neurons and cholinergic neurons, and a variety of neuronal precursor cells including neural stem cells and fetal brain cells.
Preferred among growth factors are members of the fibroblast growth factor family e. These factors may be used individually or in various combinations with RDP compositions to treat a neurological disorder. The pharmaceutical compositions each comprise one or more RDP compositions and a pharmaceutically acceptable carrier.
Included in a preferred embodiment are pharmaceutical compositions that comprise a moiety that enhances transport of an RDP composition across the blood brain barrier, the moiety being part of the carrier or conjugated to an RDP composition.
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In one embodiment of the subject method, the neuron or precursor thereof is contacted with an RDP composition prior to transplant. This contact may be in vitro, in vivo in the donor, or ex vivo, or a combination thereof. In another method, the neuron or precursor thereof is contacted with an RDP composition following transplant. In another embodiment of the method, the neuron or precursor thereof is contacted with an RDP composition both before and following transplant.
NCAM Mimetic Peptides: Potential Therapeutic Target for Neurological Disorders
Alternatively, the RDP compositions may be administered indirectly via routes which result in delivery of the composition to the afflicted tissue or organ. Animals were scored daily for clinical symptoms on a predetermined scale. Female Lewis rats were immunized with intradermal footpad injections of inoculum containing 2 mg myelin basic protein with complete Freund's adjuvant. Ten days after immunization, animals received various doses of RDP58 50, 15, or 5 mg by icv injection. A Animals were scored daily for clinical symptoms on a predetermined scale. Error bars in both graphs represent the standard error of the mean at each time point.
Representative slices were chosen from the analysis of two different animals in each group. Arrows indicate sites of concentrated infiltration. Eight days after immunization, animals received 50 mg of RDP58 by icv injection. Brain RNA from RDPtreated and control animals was analyzed for changes in gene expression thirteen days after immunization. The RDP compositions disclosed herein find use in the inhibition of their activity, and the treatment of a variety of neurological disorders including autoimmune and inflammatory neurological disorders.
The inhibition of p38 and JNK is desirable for the treatment of these neurodegenerative diseases. The presently disclosed RDP compositions have the advantageous characteristic of being JNK and p38 inhibitors that possess anti-inflammatory activity, and serve a dual role in the treatment of chronic neuroinflammatory diseases such as MS and Guillain-Barre syndrome, and acute neuroinflammatory disorders such as stroke and nervous system trauma, by inhibiting autoimmune and inflammatory process while providing a direct neuroprotective effect.
The disease appears typically in early adulthood and shows variable prognosis. The symptoms include sensory dysfunction, optic neuritis, limb weakness, gait ataxia, brain-stem symptoms, and bowel dysfunction. Patients also display increased fatigue, termed Uhthoff symptom, which correlates with increases in body temperature. The disease is characterized pathologically by the presence of focal plaques in the brain's white matter, representing regions of demyelination.
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In RRMS, remissions occur for varying lengths of time between relapses. Symptoms typically worsen and evolve into quadriparesis, cognitive decline, visual loss, and brain-stem syndromes. This progressive loss of neurological function appears to arise from irreversible injury to axons, glial scarring, and the death of oligodendrocytes.
Immunosuppressants, such as cyclosporin, suppresses the immune system as a whole, but have undesirable side effects and have not demonstrated clear efficacy in the treatment of MS. Cytotoxic immunosuppressive agents, such as mitoxanthrone and cyclophosphamide, are highly cytotoxic and have systemic side effects.
Corticosteroids generally suppress immune system activation and reduce levels of pro-inflammatory cytokines. These drugs are non-specific immunosuppressants that are used to treat acute active phases of multiple sclerosis, but they show limited effectiveness in the treatment this chronic condition. The interferons appear to suppress T-cells and inflammatory cytokines.
Glatiramer acetate, a mixture of synthetic peptides, is hypothesized to mimic myelin basic protein and appears to induce specific suppressor T-cells and suppress effector T-cells. Arthritis Rheum. Neurology Thus, according to the prior art, the use of anti-TNF agents may be ineffectual or possibly even contra-indicated.
Further, despite the availability of several immunomodulatory and immunosuppressive drugs on the market, these have only demonstrated moderate effectiveness and efficient treatments for MS patients are still in need. Thus, therapies that promote cell survival in addition to providing anti-inflammatory activity are highly desirable. EAE has been used as a model of MS in an attempt to elucidate the mechanisms of MS and test potential therapeutic agents. The complex pathogenesis of MS includes inflammation, demyelination, and potentially disabling focal lesions leading to destructive pathological changes in the central nervous system CNS.
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Most patients suffering from MS have an initial relapsing-remitting course of disease for several years before it takes on a progressive course of irreversible neurologic disability. Many of these clinical features can also be recapitulated in the various animal species used in EAE studies but on a much shorter time scale. It has been documented that relapses in MS patients correlate with inflammation and demyelination, whereas restoration of nerve function and remission are usually accompanied by resolution of inflammation and remyelination.
However, the initial mechanism for the onset of disease is largely unknown. Symptoms of Parkinson's disease include tremor, rigidity and bradykinesia. In advanced stages, patients exhibit problems with speech and a decline in cognitive function. A number of cellular and growth factor therapies have been tested with varied results.