Mechanisms of Functional Recovery After Partial Nerve Injury

部分神经损伤后功能恢复的机制

• 批准号: 8201516
• 负责人: Michael M Wang
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201516
• 关键词: Acute; Adrenal Cortex Hormones; Agonist; Animal Model; Animals; Axon; Bilateral; Biological Models; Biological Process; Cells; Clinical; Clinical Treatment; Denervation; Development; Disease; Dose; Drops; Excision; Financial compensation; Ganglia; Genetic Transcription; Glucocorticoid Receptor; Hormone Receptor; Inflammation; Inflammatory; Inflammatory Response; Injury; Lead; Measures; Medical; Melatonin; Military Personnel; Mineralocorticoid Receptor; Mutation; Nerve; Nervous System Physiology; Nervous System Trauma; Nervous system structure; Neurologic; Neuronal Injury; Neurons; Pathway interactions; Patients; Peripheral nerve injury; Pharmaceutical Preparations; Phenotype; Pineal gland; Quality of life; Rattus; Rattus norvegicus; Receptor Activation; Receptor Gene; Recovery; Recovery of Function; Rehabilitation therapy; Research; Role; Signal Pathway; Steroids; Structure of superior cervical ganglion; Testing; Time; Tissues; Traumatic Nerve Injury; Veterans; Work; axon growth; axon regeneration; combat; cytokine; disability; falls; gain of function mutation; improved; loss of function; molecular marker; nerve injury; nerve supply; neural circuit; neurological recovery; prevent; research study; response; steroid hormone; treatment strategy

DESCRIPTION (provided by applicant): Nerve injury is a common cause of permanent neurological disability in the combat military and veterans. It is well-known that victims of nerve injury follow highly variable clinical trajectories. Some patients make a full recovery, yet a very large number fail to regain normal function. Unfortunately, there are no treatments that improve chances to restore neurological function. A great deal of work has focused on encouraging axonal regrowth after nerve injury. In contrast, very little is known about how the nervous system functionally compensates after nerve damage; functional compensation therefore represents an underappreciated pathway to reducing disability from nerve injuries. We propose studies in animal models to demonstrate the efficacy of hormone receptor modulation for enhancing functional recovery without axonal growth. In preliminary work, we demonstrate a model system to study functional neuronal recovery without axon regeneration. Normally, the bilateral superior cervical ganglia (SCG) both innervate the pineal gland to stimulate nightly melatonin synthesis. In Fischer 344 (F344) rats, when we remove one SCG (1xSCGx), melatonin falls to 50% of basal levels; the day after this drop, melatonin spontaneously returns to 100% of basal levels, indicating functional recovery of the neural circuit occurs in the absence of axon regrowth. In Brown Norway (BN) rats, which carry a gain of function mutation in the mineralocorticoid receptor (MR), melatonin levels fall immediately and fail to make improvements. When BN rats are treated with corticosteroids or with antagonists of MR, rats make a rapid and permanent recovery in melatonin synthesis. These studies indicate that a neural circuit can spontaneously recover normal function without axon growth, and that steroids that act on MR or the glucocorticoid receptor (GR) are capable of enhancing functional neurological recovery. In this proposal, we will test the core hypothesis that MR antagonists and GR agonists promote function recovery when administered during specific periods after neuronal injury; we further hypothesize that MR and GR modulation after neuronal injury modifies the inflammatory response that is required for optimal compensation to neurological injury. The following specific aims will be tested. In Aim 1, we will test the time course of administration of MR antagonists for enhancing neurological recovery after partial nerve injury. In Aim 2, we will test the time course of administration of GR agonists for enhancing neurological recovery after partial nerve injury. Finally, in Aim 3, we will test the role of inflammatory cytokines on functional recovery from partial nerve injury. We hypothesize that a cascade of specific cytokines results from denervation of target tissue and that protective cytokine responses are driven by steroid hormone regulated transcription and correlate with long term functional recovery. These experiments promise to define time windows for potential clinical treatment of nerve injury and will identify molecular markers and signaling pathways that promote functional recovery after peripheral nerve injury. PUBLIC HEALTH RELEVANCE: Nerve injury is a common cause of permanent neurological disability in the combat military and veterans; unfortunately, therapies for nerve injury are limited. Improving the ability to enhance functional recovery after nerve injury offers the potential to dramatically improve the quality of life after neurological injury. We have discovered that drugs that block the mineralocorticoid receptor or activate the glucocorticoid receptor dramatically improve recovery from nerve injury in experimental animals. Herewith, we propose to study the optimal timing for administration of these drugs and to understand how these drugs influence inflammation, a key factor in nerve function recovery. The drugs we will test are already available for the treatment of other disorders. Thus, these experiments may soon lead to development of new treatments to enhance neurological recovery after traumatic nerve injury.

DESCRIPTION (provided by applicant): Nerve injury is a common cause of permanent neurological disability in the combat military and veterans. It is well-known that victims of nerve injury follow highly variable clinical trajectories. Some patients make a full recovery, yet a very large number fail to regain normal function. Unfortunately, there are no treatments that improve chances to restore neurological function. A great deal of work has focused on encouraging axonal regrowth after nerve injury. In contrast, very little is known about how the nervous system functionally compensates after nerve damage; functional compensation therefore represents an underappreciated pathway to reducing disability from nerve injuries. We propose studies in animal models to demonstrate the efficacy of hormone receptor modulation for enhancing functional recovery without axonal growth. In preliminary work, we demonstrate a model system to study functional neuronal recovery without axon regeneration. Normally, the bilateral superior cervical ganglia (SCG) both innervate the pineal gland to stimulate nightly melatonin synthesis. In Fischer 344 (F344) rats, when we remove one SCG (1xSCGx), melatonin falls to 50% of basal levels; the day after this drop, melatonin spontaneously returns to 100% of basal levels, indicating functional recovery of the neural circuit occurs in the absence of axon regrowth. In Brown Norway (BN) rats, which carry a gain of function mutation in the mineralocorticoid receptor (MR), melatonin levels fall immediately and fail to make improvements. When BN rats are treated with corticosteroids or with antagonists of MR, rats make a rapid and permanent recovery in melatonin synthesis. These studies indicate that a neural circuit can spontaneously recover normal function without axon growth, and that steroids that act on MR or the glucocorticoid receptor (GR) are capable of enhancing functional neurological recovery. In this proposal, we will test the core hypothesis that MR antagonists and GR agonists promote function recovery when administered during specific periods after neuronal injury; we further hypothesize that MR and GR modulation after neuronal injury modifies the inflammatory response that is required for optimal compensation to neurological injury. The following specific aims will be tested. In Aim 1, we will test the time course of administration of MR antagonists for enhancing neurological recovery after partial nerve injury. In Aim 2, we will test the time course of administration of GR agonists for enhancing neurological recovery after partial nerve injury. Finally, in Aim 3, we will test the role of inflammatory cytokines on functional recovery from partial nerve injury. We hypothesize that a cascade of specific cytokines results from denervation of target tissue and that protective cytokine responses are driven by steroid hormone regulated transcription and correlate with long term functional recovery. These experiments promise to define time windows for potential clinical treatment of nerve injury and will identify molecular markers and signaling pathways that promote functional recovery after peripheral nerve injury. PUBLIC HEALTH RELEVANCE: Nerve injury is a common cause of permanent neurological disability in the combat military and veterans; unfortunately, therapies for nerve injury are limited. Improving the ability to enhance functional recovery after nerve injury offers the potential to dramatically improve the quality of life after neurological injury. We have discovered that drugs that block the mineralocorticoid receptor or activate the glucocorticoid receptor dramatically improve recovery from nerve injury in experimental animals. Herewith, we propose to study the optimal timing for administration of these drugs and to understand how these drugs influence inflammation, a key factor in nerve function recovery. The drugs we will test are already available for the treatment of other disorders. Thus, these experiments may soon lead to development of new treatments to enhance neurological recovery after traumatic nerve injury.