tacrolimus and Neurodegenerative-Diseases

Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, and the discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. To investigate the pathomechanism of tauopathies, we generated and studied P301S mutant human tau transgenic mice (line PS19). Filamentous tau lesions developed in PS19 mice at 6-months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age. Remarkably, hippocampal synapse loss and impaired synaptic function were detected in 3 month old PS19 mice before fibrillary tau tangles emerged. Prominent microglial activation and proinflammatory cytokine expressions in neurons also preceded tangle formation. Importantly, immunosuppression of young PS19 mice with FK506 attenuated tau pathology, thereby linking neuroinflammation to early progression of tauopathies. Recently, an anti-inflammatory function of acetylcholine (ACh) has been reported, suggesting that synaptic dysfunction might accelerate neuroinflammatory reaction by depletion of ACH. To investigate this, we administered donepezil (DZ), an ACh-esterase inhibitor, and trihexiphenidyl (TP), an anti-cholinergic agent to PS19 mice. Interestingly, DZ ameliorated but TP deteriorated microglial activation, tau pathology and neuronal loss, indicating the ACh level in the brain might play roles in not only neurotransmission, but also suppressing neuroinflammation in the brain.

Topics: Acetylcholine; Amyloid; Animals; Brain; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Humans; Immunosuppressive Agents; Indans; Inflammation; Mice; Mice, Transgenic; Microglia; Mutation; Neurodegenerative Diseases; Piperidines; Synapses; Tacrolimus; tau Proteins

No clinical techniques induce restoration of neurological losses following spinal cord trauma. Peripheral nerve damage also leads to permanent neurological deficits, but neurological recovery can be relatively good, especially if the ends of a transected nerve are anastomosed soon after the injury. The time until recovery generally depends on the distance the axons must regenerate to their targets. Neurological recovery following the destruction of a length of a peripheral nerve requires a graft to bridge the gap that is permissive to, and promotes, axon regeneration. But neurological recovery is slow and limited, especially for gaps longer than 1.5 cm, even using autologous peripheral nerve grafts. Without a reliable means of bridging long nerve gaps, such injuries commonly result in amputations. Promoting extensive neurological recovery requires techniques that simultaneously provide protection to injured neurons and increase the numbers of neurons that extend axons, while inducing more rapid and extensive axon regeneration across long nerve gaps. Although conduits filled with various materials enhance axon regeneration across short nerve gaps, pure sensory nerve graft remains the gold standard for use across long nerve gaps, even though they lead to only limited neurological recovery. Consistent results demonstrate that several immunosuppressive agents enhance the number of axons and the rate at which they regenerate. This review examines the roles played by immunosuppressants, especially FK506, with primary focus on its role as a neuroprotectant and neurotrophic agent, and its potential clinical use to promote improved neurological recovery following peripheral nerve and spinal cord injuries.

Topics: Animals; Axons; Drug Administration Schedule; Humans; Immunophilins; Immunosuppressive Agents; Ischemia; Nerve Regeneration; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Spinal Cord Injuries; Tacrolimus

Immunophilins are a family of proteins mainly known because they act as receptors of the immunosuppressant drugs cyclosporin A (CsA) and FK506. Immunophilins serve several general functions, including regulation of mitochondrial permeability, modulation of ion channels stability and acting as chaperones for a variety of proteins. However, immunophilins are also present at high density in the nervous system. CsA, FK506 and other derivatives inhibit the function of immunophilins and, through bloking or activating several intracellular pathways, it has been shown that they exert neuroprotective effects in different experimental models of ischemia, Parkinson's disease and excitotoxic insults. Moreover, FK506 also has neuroregenerative effects, by enhancing the axonal regeneration rate after lesions of the peripheral nervous system. The development of new agents that selectively bind to immunophilins opens new interesting perspectives for the therapy of degenerative diseases and injuries of the nervous system.

Topics: Animals; Calcineurin; Calcium Channels; Central Nervous System; Cyclosporine; Humans; Immunophilins; Immunosuppressive Agents; Ligands; Models, Biological; Nerve Regeneration; Neurodegenerative Diseases; Neuroprotective Agents; Receptors, Steroid; Receptors, Transforming Growth Factor beta; Tacrolimus

The immunophilins are a family of proteins that are receptors for immunosuppressant drugs, such as cyclosporin A, FK506, and rapamycin. They occur in two classes, the FK506-binding proteins (FKBPs), which bind FK506 and rapamycin, and the cyclophilins, which bind cyclosporin A. Immunosuppressant actions of cyclosporin A and FK506 derive from the drug-immunophilin complex binding to and inhibiting the phosphatase calcineurin. Rapamycin binds to FKBP and the complex binds to Rapamycin And FKBP-12 Target (RAFT). RAFT affects protein translation by phosphorylating p70-S6 kinase, which phosphorylates the ribosomal S6 protein, and 4E-BP1, a repressor of protein translation initiation. Immunophilin levels are much higher in the brain than in immune tissues, and levels of FKBP12 increase in regenerating neurons in parallel with GAP-43. Immunophilin ligands, including nonimmunosuppressants that do not inhibit calcineurin, stimulate regrowth of damaged peripheral and central neurons, including dopamine, serotonin, and cholinergic neurons in intact animals. FKPB12 is physiologically associated with the ryanodine and inositol 1,4,5-trisphosphate (IP3) receptors and regulates their calcium flux. By influencing phosphorylation of neuronal nitric oxide synthase, FKBP12 regulates nitric oxide formation, which is reduced by FK506.

Topics: Animals; Calcineurin Inhibitors; Carrier Proteins; Chickens; Cyclosporine; DNA-Binding Proteins; Heat-Shock Proteins; Humans; Immunosuppressive Agents; Lymphocyte Activation; Models, Immunological; Nerve Regeneration; Nerve Tissue Proteins; Neurodegenerative Diseases; Neuroprotective Agents; Neurotoxins; Nitric Oxide Synthase; Peptidylprolyl Isomerase; Phosphotransferases (Alcohol Group Acceptor); Polyenes; Rats; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Sirolimus; T-Lymphocytes, Cytotoxic; Tacrolimus; Tacrolimus Binding Proteins; TOR Serine-Threonine Kinases

Topics: Animals; Autophagy; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Models, Molecular; MPTP Poisoning; Neurodegenerative Diseases; PC12 Cells; Rats; Sirolimus; Tacrolimus; Zebrafish

Abnormal accumulation of amyloid β (Aβ), α-synuclein (α-syn), and microtubule-associated protein tau (tau) have been implicated in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Pick's disease (PiD). The mechanisms through which aggregated versions of α-syn, Aβ, and tau may lead to neurodegeneration are not entirely clear, however, there is emerging evidence that neuronal calcium dysregulation is at play. Two-photon microscopy is a powerful tool that can be used to measure in vivo alterations of calcium transients using animal models of neurodegeneration, and when coupled with statistical methods to characterize functional signals, can reveal features that identify and discern between distinct mouse types. We studied four mouse models of neurodegenerative diseases, wild-type (WT) α-syn, E57K α-syn, amyloid precursor protein (APP), and triple-repeat (3R)-Tau and Non-transgenic (tg) littermates using two-photon microscopy. We found that for calcium transients, simple measures such as area under the curve (AUC) and peak width in the 1-Hz whisker pad stimulation paradigm, were significantly increased for WT α-syn, E57K α-syn and APP mice across all cortical depths compared to Non-tg mice. A similar result was found in the 3-Hz paradigm in E57K α-syn mice. Spontaneous calcium transient AUC was significantly higher in WT α-syn mice and lower for APP and 3R Tau mice at 150-μm depth. Going beyond simple measure differences such as group means for AUC, signal peak width, and spontaneous calcium activity counts, we built statistical classifiers to characterize neuronal calcium signals to identify and discern, with quantified measures of confidence, all mouse types. We tested our classifier with FK506, which regulates mitochondrial calcium and found that this drug modulated the WT α-syn calcium transients to such an extent that the classifier easily identified the calcium transients as belonging to Non-tg mice. The coupling of two-photon microscopy data and statistical classifiers serves to effectively create a bioassay where the number of animals and scientific resources can be reduced without compromising the results of the experiment.

Topics: alpha-Synuclein; Amyloid beta-Protein Precursor; Animals; Calcineurin Inhibitors; Calcium Signaling; Cluster Analysis; Disease Models, Animal; Female; Mice; Mice, Transgenic; Neurodegenerative Diseases; Physical Stimulation; ROC Curve; Somatosensory Cortex; Tacrolimus; tau Proteins; Vibrissae

Topics: Animals; Apoptosis; Benzimidazoles; Brain; Cell Survival; Fluorescent Dyes; Free Radicals; Glioma; Glutathione; Hydrogen Peroxide; Immunophilins; Immunosuppressive Agents; Ligands; Neurodegenerative Diseases; Neuroglia; Neuroprotective Agents; Oxidative Stress; Pyrrolidines; Rats; Tacrolimus; Tumor Cells, Cultured; Up-Regulation

Topics: Animals; Carrier Proteins; Disease Models, Animal; DNA-Binding Proteins; Heat-Shock Proteins; Humans; Hydroxydopamines; Ligands; Neurodegenerative Diseases; Parkinson Disease; Peptidylprolyl Isomerase; Tacrolimus; Tacrolimus Binding Proteins