Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0599766 (functional recovery)
 13,441 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclosporin A (CsA) has direct effects on neural stem and progenitor cells (together termed neural precursor cells; NPCs) in the adult central nervous system. Administration of CsA in vitro or in vivo promotes the survival of NPCs and expands the pools of NPCs in mice. Moreover, CsA administration is effective in promoting NPC activation, tissue repair and functional recovery in a mouse model of cortical stroke. The mechanism(s) by which CsA mediates this cell survival effect remains unknown. Herein, we examined both calcineurin-dependent and calcineurin-independent pathways through which CsA might mediate NPC survival. To examine calcineurin-dependent pathways, we utilized FK506 (Tacrolimus), an immunosuppressive molecule that inhibits calcineurin, as well as drugs that inhibit cyclophilin A-mediated activation of calcineurin. To evaluate the calcineurin-independent pathway, we utilized NIM811, a non-immunosuppressive CsA analog that functions independently of calcineurin by blocking mitochondrial permeability transition pore formation. We found that only NIM811 can entirely account for the pro-survival effects of CsA on NPCs. Indeed, blocking signaling pathways downstream of calcineurin activation using nNOS mice did not inhibit CsA-mediated cell survival, which supports the proposal that the effects are calcinuerin-independent. In vivo studies revealed that NIM811 administration mimics the pro-survival effects of CsA on NPCs and promotes functional recovery in a model of cortical stroke, identical to the effects seen with CsA administration. We conclude that CsA mediates its effect on NPC survival through calcineurin-independent inhibition of mitochondrial permeability transition pore formation and suggest that this pathway has potential therapeutic benefits for developing NPC-mediated cell replacement strategies.
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PMID:Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway. 2505 98

Traumatic injuries of the peripheral nerves are very common. Surgical repair of the damaged nerve is often complicated by scar tissue formation around the damaged nerve itself. The main objective of this study is to present the recent data from animal experimental studies where pharmacological topical agents are used at the site of peripheral nerve repair. Some of the most commonly topical agents used are tacrolimus (FK506), hyaluronic acid and its derivatives, and melatonin, whereas methylprednisolone and vitamin B12 have been used less. These studies have shown that the abovementioned substances have neuroprotective and neuroregenerative properties though different mechanisms. The successes of the regenerative process of the nerve repair in experimental research, using topical agents, can be evaluated using variety of methods such as morphological, electrophysiologic, and functional evaluation. However, most authors agree that despite good microsurgical repair and topical application of these substances, full regeneration and functional recovery of the nerve injured are almost never achieved.
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PMID:Application of topical pharmacological agents at the site of peripheral nerve injury and methods used for evaluating the success of the regenerative process. 2530 79

Dark Agouti rat donor hind limbs were orthotopically transplanted into Lewis rat recipients to verify the effects of bone marrow mesenchymal stem cells on neural regeneration and functional recovery of allotransplanted limbs in the microenvironment of immunotolerance. bone marrow mesenchymal stem cells were intramuscularly (gluteus maximus) injected with FK506 (tacrolimus) daily, and were transplanted to the injured nerves. Results indicated that the allograft group not receiving therapy showed severe rejection, with transplanted limbs detaching at 10 days after transplantation with complete necrosis. The number of myelinated axons and Schwann cells in the FK506 and FK506 + bone marrow mesenchymal stem cells groups were significantly increased. We observed a lesser degree of gastrocnemius muscle degeneration, and increased polymorphic fibers along with other pathological changes in the FK506 + bone marrow mesenchymal stem cells group. The FK506 + bone marrow mesenchymal stem cells group showed significantly better recovery than the autograft and FK506 groups. The results demonstrated that FK506 improved the immune microenvironment. FK506 combined with bone marrow mesenchymal stem cells significantly promoted sciatic nerve regeneration, and improved sensory recovery and motor function in hind limb allotransplant.
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PMID:Use of FK506 and bone marrow mesenchymal stem cells for rat hind limb allografts. 2533 14

Despite substantial improvement in microsurgical techniques for nerve repair, recovery after peripheral nerve injury is usually incomplete. FK506, an FDA approved immunosuppressant, improves functional recovery and reinnervation following peripheral nerve injury in animal models. However, systemically delivered FK506 causes undesirable global immunosuppression. We have, therefore, engineered a biodegradable local delivery system for FK506 using fibrin gel as a drug reservoir that could be placed at a site of nerve injury. FK506 was incorporated into fibrin gel in solubilized, particulated, and poly(lactic-co-glycolic) acid (PLGA) microspheres-encapsulated forms. A tunable release of FK506 in the fibrin gel from days to weeks was observed with the rate of release being most rapid for the solubilized form and then the particulate form. The most prolonged period of release was seen with the PLGA microsphere-encapsulated form. As analyzed by in vitro dorsal root ganglion (DRG) neurite extension assay, PLGA microsphere encapsulation of FK506 did not alter the drug's properties and the released FK506 maintained its bioactivity over the entire period of release. This study suggests that local delivery of FK506 with fibrin hydrogel could be used to enhance peripheral nerve regeneration.
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PMID:A novel polymeric drug delivery system for localized and sustained release of tacrolimus (FK506). 2585 Jun 93

The present study aimed to evaluate whether the application of tacrolimus (FK506) could improve functional recovery in spinal cord injury (SCI) rat models by activating astrocytes, and to further investigate the underlying mechanisms of this action. Male Sprague-Dawley rats (n=56) were used to establish moderate SCI models, which were induced at the T10 spinal segment by dropping a 10-g weight from a height of 25 mm using a New York University Impactor device. The rats were randomly separated into the FK506 or control group (n=28 per group). Rats were treated with FK506 (0.5 mg/kg) or saline intravenously 30 min after sustaining the injury. Functional recovery was evaluated over 42 days following the injury, and epidermal growth factor (EGF) levels were detected. The astrocytes were treated with FK506 in vitro, and the EGF mRNA and protein expression levels were analyzed using reverse transcription-quantitative polymerase chain reaction and ELISA, respectively. DNA microarray analysis was also performed to evaluate the genes in astrocytes. Rats in the FK506 group had improved locomotor functional recovery compared with those of control group. Furthermore, FK506 upregulated EGF expression of astrocytes both in vivo and in vitro. Subsequent to treatment with FK506-conditioned medium (CM), the length of neuronal cells increased 61.06% on the first day, and increased 56.4% on the third day compared with those of C-CM group. Furthermore, addition of anti-EGF neutralizing antibodies could interrupt the promotion of neurite outgrowth by FK506-CM. The present study indicates that astrocytes have an important role as mediators of FK506-improved spinal cord function recovery, and this partially clarifies the role of cell-cell interaction through modulating EGF in this process.
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PMID:Analysis of FK506-mediated functional recovery and neuroprotection in a rat model of spinal cord injury indicates that EGF is modulated in astrocytes. 3011 8

Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate and line the endoneurial tubes to guide and support regenerating axons. The axons emerge from the stump of the viable nerve attached to the neuronal soma. The SCs downregulate myelin-associated genes and concurrently, upregulate growth-associated genes that include neurotrophic factors as do the injured neurons. However, the gene expression is transient and progressively fails to support axon regeneration within the SC-containing endoneurial tubes. Moreover, despite some preference of regenerating motor and sensory axons to "find" their appropriate pathways, the axons fail to enter their original endoneurial tubes and to reinnervate original target organs, obstacles to functional recovery that confront nerve surgeons. Several surgical manipulations in clinical use, including nerve and tendon transfers, the potential for brief low-frequency electrical stimulation proximal to nerve repair, and local FK506 application to accelerate axon outgrowth, are encouraging as is the continuing research to elucidate the molecular basis of nerve regeneration.
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PMID:Peripheral Nerve Regeneration and Muscle Reinnervation. 3321 95


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