Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since CXCL12 and its receptors, CXCR4 and CXCR7, have been found in the brain, the role of this chemokine has been expanded from chemoattractant in the immune system to neuromodulatory in the brain. Several pieces of evidence suggest that this chemokine system could crosstalk with the GABAergic system, known to be the main inhibitory neurotransmitter system in the brain. Indeed, GABA and CXCL12 as well as their receptors are colocalized in many cell types including neurons and there are several examples in which these two systems interact. Several mechanisms can be proposed to explain how these systems interact, including receptor-receptor interactions, crosstalk at the level of second messenger cascades, or direct pharmacological interactions, as GABA and GABAB receptor agonists/antagonists have been shown to be allosteric modulators of CXCR4. The interplay between CXCL12/CXCR4-CXCR7 and GABA/GABAA-GABAB receptors systems could have many physiological implications in neurotransmission, cancer and inflammation. In addition, the GABAB agonist baclofen is currently used in medicine to treat spasticity in patients with spinal cord injury, cerebral palsy, traumatic brain injury, multiple sclerosis, and other disorders. More recently it has also been used in the treatment of alcohol dependence and withdrawal. The allosteric effects of this agent on CXCR4 could contribute to these beneficial effects or at the opposite, to its side effects.
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PMID:CXCL12 chemokine and GABA neurotransmitter systems crosstalk and their putative roles. 2480 25

Injury to the adult nervous system promotes the expression and secretion of brain-derived neurotrophic factor (BDNF). Because it promotes neuronal growth, survival and neurogenesis, BDNF may initiate compensatory processes that mitigate the deleterious effects of injury, disease or stress. Despite this, BDNF has been implicated in several injury-induced maladaptive processes including pain, spasticity and convulsive activity. This review will concentrate on the predominant role of BDNF in the initiation and maintenance of chronic and/or neuropathic pain at the spinal, peripheral and central levels. Within the spinal dorsal horn, the pattern of BDNF-induced changes in synaptic transmission across five different, identified neuronal phenotypes bears a striking resemblance to that produced by chronic constriction injury (CCI) of peripheral nerves. The appearance of this "pain footprint" thus reflects multiple sensitizing actions of microglial-derived BDNF. These include changes in the chloride equilibrium potential, decreased excitatory synaptic drive to inhibitory neurons, complex changes in inhibitory (GABA/glycinergic) synaptic transmission, increases in excitatory synaptic drive to excitatory neurons and the appearance of oscillatory activity. BDNF effects are confined to changes in synaptic transmission as there is little change in the passive or active properties of neurons in the superficial dorsal horn. Actions of BDNF in the brain stem and periphery also contribute to the onset and persistence of chronic pain. In spite of its role in compensatory processes that facilitate the recovery of the nervous system from injury, the widespread maladaptive actions of BDNF mean that there is literally "no gain without pain".
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PMID:BDNF: no gain without pain? 2488 39

4-Aminobutyric acid is an inhibitory neurotransmitter involved in the control of neuronal activity in the mammalian central nervous system. There is considerable direct and indirect evidence that impaired activity of GABAmediated inhibitory synapses may be an important causative factor in experimental and clinical seizure disorders. This review is focused on the recent development of compounds which can influence GABA neurotransmission by affecting the GABA receptors, the plasma-membrane GABA transporters (GATs) and catabolic enzyme GABA-transaminase (GABAT). These compounds have been primarily investigated in relation to epilepsy, but it has also been found that a decrease in GABA neurotransmission appears to be involved in the aetiology of several neurological disorders such as insomnia, spasticity, neuropathic pain, anxiety and other mental disorders.
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PMID:GABA system as a target for new drugs. 2493 45

Activity-based therapies are routinely integrated in spinal cord injury (SCI) rehabilitation programs because they result in a reduction of hyperreflexia and spasticity. However, the mechanisms by which exercise regulates activity in spinal pathways to reduce spasticity and improve functional recovery are poorly understood. Persisting alterations in the action of GABA on postsynaptic targets is a signature of CNS injuries, including SCI. The action of GABA depends on the intracellular chloride concentration, which is determined largely by the expression of two cation-chloride cotransporters (CCCs), KCC2 and NKCC1, which serve as chloride exporters and importers, respectively. We hypothesized that the reduction in hyperreflexia with exercise after SCI relies on a return to chloride homeostasis. Sprague Dawley rats received a spinal cord transection at T12 and were assigned to SCI-7d, SCI-14d, SCI-14d+exercise, SCI-28d, SCI-28d+exercise, or SCI-56d groups. During a terminal experiment, H-reflexes were recorded from interosseus muscles after stimulation of the tibial nerve and the low-frequency-dependent depression (FDD) was assessed. We provide evidence that exercise returns spinal excitability and levels of KCC2 and NKCC1 toward normal levels in the lumbar spinal cord. Acutely altering chloride extrusion using the KCC2 blocker DIOA masked the effect of exercise on FDD, whereas blocking NKCC1 with bumetanide returned FDD toward intact levels after SCI. Our results indicate that exercise contributes to reflex recovery and restoration of endogenous inhibition through a return to chloride homeostasis after SCI. This lends support for CCCs as part of a pathway that could be manipulated to improve functional recovery when combined with rehabilitation programs.
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PMID:Exercise modulates chloride homeostasis after spinal cord injury. 2499 Sep 18

The central pattern generators (CPGs) for locomotion, located in the lumbar spinal cord, are functional at birth in the rat. Their maturation occurs during the last few days preceding birth, a period during which the first projections from the brainstem start to reach the lumbar enlargement of the spinal cord. Locomotor burst activity in the mature intact spinal cord alternates between flexor and extensor motoneurons through reciprocal inhibition and between left and right sides through commisural inhibitory interneurons. By contrast, all motor bursts are in phase in the fetus. The alternating pattern disappears after neonatal spinal cord transection which suppresses supraspinal influences upon the locomotor networks. This article will review the role of serotonin (5-HT), in particular 5-HT2 receptors, in shaping the alternating pattern. For instance, pharmacological activation of these receptors restores the left-right alternation after injury. Experiments aimed at either reducing the endogenous level of serotonin in the spinal cord or blocking the activation of 5-HT2 receptors. We then describe recent evidence that the action of 5-HT2 receptors is mediated, at least in part, through a modulation of chloride homeostasis. The postsynaptic action of GABA and glycine depends on the intracellular concentration of chloride ions which is regulated by a protein in the plasma membrane, the K(+)-Cl(-) cotransporter (KCC2) extruding both K(+) and Cl(-) ions. Absence or reduction of KCC2 expression leads to a depolarizing action of GABA and glycine and a marked reduction in the strength of postsynaptic inhibition. This latter situation is observed early during development and in several pathological conditions, such as after spinal cord injury, thereby causing spasticity and chronic pain. It was recently shown that specific activation of 5-HT2A receptors is able to up-regulate KCC2, restore endogenous inhibition and reduce spasticity.
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PMID:Serotonergic modulation of post-synaptic inhibition and locomotor alternating pattern in the spinal cord. 2522 77

Severe spastic tone and/or spastic hypertonia can be the most disabling consequences of a neurologic insult, resulting from an excess of muscle tone. Baclofen, a GABA-B agonist, is one of the most widely used drugs in treating abnormal or disabling spastic tone. However, the effectiveness of baclofen taken orally is often limited by its systemic side effects, including sedation, confusion, and lethargy. Intrathecal baclofen (ITB) delivered by an implanted catheter can work directly at the spinal cord level to reduce spastic tone through presynaptic inhibition. Several decades after Penn and Kroin (1984) proved that continuous infusion of intrathecal baclofen reduced spinal cord spasticity, numerous studies have demonstrated the benefits of ITB therapy and proven its effectiveness in modulating and reducing spastic tone. In this article the authors review current methods of management with ITB therapy; summarize the current knowledge, controversies, and available scientific literature; illustrate through different clinical cases treatment strategies and their outcomes; and lastly, provide a synopsis of current clinical practice in ITB therapy with insights into new therapeutic developments.
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PMID:Spasticity and intrathecal baclofen. 2552 30

Baclofen is used clinically as a drug that treats spasticity, which is a syndrome characterized by excessive contraction of the muscles and hyperflexia in the central nervous system (CNS), by activating GABA(B) receptors (GABA(B)Rs). Baclofen was recently reported to desensitize chemokine receptors and to suppress inflammation through the activation of GABA(B)Rs. GABA(B)Rs are expressed in various immune cells, but the functions of these receptors in autoimmune diseases remain largely unknown. In this study, we investigated the effects of baclofen in murine collagen-induced arthritis (CIA). Oral administration of baclofen alleviated the clinical development of CIA, with a reduced number of IL-17-producing T helper 17 (T(H)17) cells. In addition, baclofen treatment suppressed dendritic cell (DC)-primed T(H)17 cell differentiation by reducing the production of IL-6 by DCs in vitro. Furthermore, the pharmacological and genetic blockade of GABA(B)Rs in DCs weakened the effects of baclofen, indicating that GABA(B)Rs are the molecular targets of baclofen on DCs. Thus, our findings revealed a potential role for baclofen in the treatment of CIA, as well as a previously unknown signaling pathway that regulates DC function.
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PMID:The anti-spasticity drug baclofen alleviates collagen-induced arthritis and regulates dendritic cells. 2555 30

The effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) on spasticity following spinal cord injury (SCI) and the action mechanism were investigated. SCI models were established in Sprague-Dawley rats. Five groups were set up: normal control group, SCI-7 day (7D) model group, SCI-14D model group, SCI-7D rTMS group and SCI-14D rTMS group (n=10 each). The rats in SCI rTMS groups were treated with 10 Hz rTMS at 8th day and 15th day after SCI respectively. Motor recovery and spasticity alleviation were evaluated by BBB scale once a week till the end of treatment. Finally, different parts of tissues were dissected out for detection of GABA receptors using Western blotting and polymerase chain reaction (PCR) technique. The results showed that the BBB scores after treatment were significantly higher in SCI-7D rTMS group than in SCI-14D rTMS group (P<0.05). The GABA receptors were down-regulated more significantly in SCI-14D model group than in SCI-7D model group (P<0.05). At different time points, rTMS treatment could affect the up-regulation of GABA receptors: The up-regulation of GABA receptors was more obvious in SCI-7D rTMS group than in SCI-14D rTMS treatment group (P<0.05). It was concluded that 10-Hz rTMS could alleviate spasticity following SCI and promote the motor recovery in rats, which might be attributed to the up-regulation of GABA receptors. It was also suggested that early high-frequency rTMS treatment after SCI may achieve more satisfactory curative effectiveness.
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PMID:Mechanism of GABA receptors involved in spasticity inhibition induced by transcranial magnetic stimulation following spinal cord injury. 2587 59

Baclofen is a highly used centrally acting GABA agonist that continues to be an effective therapy for spasticity and chronic hiccups. The renally dependent excretion determines the circulating concentrations and guides effective dosing to decrease adverse reactions. Caution should be considered in administering baclofen to patients with decreased renal function. We present a patient with end stage renal disease on hemodialysis with recent baclofen ingestion who presented with toxic encephalopathy that was resolved with additional dialysis sessions.
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PMID:Baclofen-Induced Encephalopathy in End Stage Renal Disease. 2629 12

Baclofen is a gamma- aminobutyric acid B (GABA B) agonist used for the management of spasticity associated with spinal cord injury. Oral baclofen might cause constipation, but intestinal pseudo-obstruction is very rare. We report a 50-year-old male with spasticity following cervical discectomy (C3-4) on oral baclofen for 6 months with intestinal pseudo-obstruction. He had undergone open suprapubic cystostomy for traumatic urethral injury, 45 days prior to the presentation and adhesive intestinal obstruction was also considered a possibility. However, there were no air fluid levels on abdominal radiographs and ultrasound abdomen was non-contributory. Withdrawal of baclofen was therapeutic in this patient. This case is being reported to highlight the rare possibility of oral baclofen induced intestinal pseudo-obstruction.
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PMID:Intestinal pseudo-obstruction following oral baclofen: An unusual complication. 2631 4


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