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1.
Nat Neurosci ; 22(8): 1269-1275, 2019 08.
Article in English | MEDLINE | ID: mdl-31235933

ABSTRACT

Inhibitory extracellular matrices form around mature neurons as perineuronal nets containing chondroitin sulfate proteoglycans that limit axonal sprouting after CNS injury. The enzyme chondroitinase (Chase) degrades inhibitory chondroitin sulfate proteoglycans and improves axonal sprouting and functional recovery after spinal cord injury in rodents. We evaluated the effects of Chase in rhesus monkeys that had undergone C7 spinal cord hemisection. Four weeks after hemisection, we administered multiple intraparenchymal Chase injections below the lesion, targeting spinal cord circuits that control hand function. Hand function improved significantly in Chase-treated monkeys relative to vehicle-injected controls. Moreover, Chase significantly increased corticospinal axon growth and the number of synapses formed by corticospinal terminals in gray matter caudal to the lesion. No detrimental effects were detected. This approach appears to merit clinical translation in spinal cord injury.


Subject(s)
Chondroitinases and Chondroitin Lyases/therapeutic use , Spinal Cord Injuries/drug therapy , Animals , Axons/pathology , Chondroitinases and Chondroitin Lyases/administration & dosage , Chondroitinases and Chondroitin Lyases/adverse effects , Gray Matter/pathology , Hand/innervation , Hand/physiopathology , Injections, Intralesional , Macaca mulatta , Male , Microglia/pathology , Motor Neurons/pathology , Psychomotor Performance , Pyramidal Tracts/pathology , Recovery of Function , Spinal Cord Injuries/physiopathology , Swine , Synapses/pathology , Treatment Outcome
2.
Toxicol Sci ; 161(2): 401-411, 2018 02 01.
Article in English | MEDLINE | ID: mdl-29069498

ABSTRACT

GGF2 is a recombinant human neuregulin-1ß in development for chronic heart failure. Phase 1 clinical trials of GGF2 were put on hold when transient elevations in serum aminotransferases and total bilirubin were observed in 2 of 43 subjects who received single doses of GGF2 at 1.5 or 0.378 mg/kg. However, aminotransferase elevations were modest and not typical of liver injury sufficient to result in elevated serum bilirubin. Cynomolgus monkeys administered a single 15 mg/kg dose of GGF2 had similar transient elevations in serum aminotransferases and bilirubin as well as transient elevations in serum bile acids. However, no hepatocellular necrosis was observed in liver biopsies obtained during peak elevations. When sandwich-cultured human hepatocytes were treated with GGF2 for up to 72 h at concentrations approximately 0.8-fold average plasma Cmax for the 0.378 mg/kg dose, no cytotoxicity was observed. Gene expression profiling identified approximately 50% reductions in mRNAs coding for bilirubin transporters and bile acid conjugating enzymes, as well as changes in expression of additional genes mimicking the interleukin-6-mediated acute phase response. Similar gene expression changes were observed in GGF2-treated HepG2 cells and primary monkey hepatocytes. Additional studies conducted in sandwich-cultured human hepatocytes revealed a transient and GGF2 concentration-dependent decrease in hepatocyte bile acid content and biliary clearance of taurocholate without affecting biliary taurocholate efflux. Taken together, these data suggest that GGF2 does not cause significant hepatocellular death, but transiently modifies hepatic handling of bilirubin and bile acids, effects that may account for the elevations in serum bilirubin observed in the clinical trial subjects.


Subject(s)
Bile Acids and Salts/blood , Bile Ducts/drug effects , Bilirubin/blood , Hepatocytes/drug effects , Liver/drug effects , Neuregulin-1/adverse effects , Animals , Bile Ducts/metabolism , Bile Ducts/pathology , Biological Transport , Cell Survival/drug effects , Clinical Trials, Phase I as Topic , Cytochrome P-450 CYP3A/genetics , Hep G2 Cells , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Liver/metabolism , Liver/pathology , Macaca fascicularis , Male , Primary Cell Culture , Toxicogenetics , Transcriptome/drug effects
3.
Neurorehabil Neural Repair ; 31(4): 387-396, 2017 04.
Article in English | MEDLINE | ID: mdl-28107804

ABSTRACT

BACKGROUND: 4-Aminopyridine (4-AP) is a Food and Drug Administration-approved drug to improve motor function in people with multiple sclerosis. Preliminary results suggest the drug may act on intact neural circuits and not just on demyelinated ones. OBJECTIVE: To determine if 4-AP at clinically relevant levels alters the excitability of intact motor circuits. METHODS: In anesthetized rats, electrodes were placed over motor cortex and the dorsal cervical spinal cord for electrical stimulation, and electromyogram electrodes were inserted into biceps muscle to measure responses. The motor responses to brain and spinal cord stimulation were measured before and for 5 hours after 4-AP administration both in uninjured rats and rats with a cut lesion of the pyramidal tract. Blood was collected at the same time as electrophysiology to determine drug plasma concentration with a goal of 20 to 100 ng/mL. RESULTS: We first determined that a bolus infusion of 0.32 mg/kg 4-AP was optimal: it produced on average 61.5 ± 1.8 ng/mL over the 5 hours after infusion. This dose of 4-AP increased responses to spinal cord stimulation by 1.3-fold in uninjured rats and 3-fold in rats with pyramidal tract lesion. Responses to cortical stimulation also increased by 2-fold in uninjured rats and up to 4-fold in the injured. CONCLUSION: Clinically relevant levels of 4-AP strongly augment physiological responses in intact circuits, an effect that was more robust after partial injury, demonstrating its broad potential in treating central nervous system injuries.


Subject(s)
4-Aminopyridine/pharmacology , Central Nervous System Agents/pharmacology , Cervical Cord/drug effects , Motor Cortex/drug effects , Pyramidal Tracts/drug effects , Spinal Cord Injuries/drug therapy , 4-Aminopyridine/blood , 4-Aminopyridine/pharmacokinetics , Animals , Central Nervous System Agents/blood , Central Nervous System Agents/pharmacokinetics , Cervical Cord/injuries , Cervical Cord/physiology , Cervical Cord/physiopathology , Drug Evaluation, Preclinical , Electric Stimulation , Electromyography , Evoked Potentials, Motor/drug effects , Evoked Potentials, Motor/physiology , Female , Forelimb/drug effects , Forelimb/physiology , Forelimb/physiopathology , Microelectrodes , Motor Cortex/physiology , Motor Cortex/physiopathology , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiology , Muscle, Skeletal/physiopathology , Pyramidal Tracts/injuries , Pyramidal Tracts/physiology , Pyramidal Tracts/physiopathology , Random Allocation , Rats, Sprague-Dawley , Spinal Cord Injuries/physiopathology
4.
Eur J Pharmacol ; 796: 76-89, 2017 Feb 05.
Article in English | MEDLINE | ID: mdl-27993643

ABSTRACT

Neuregulins are important growth factors involved in cardiac development and response to stress. Certain isoforms and fragments of neuregulin have been found to be cardioprotective. The effects of a full-length neuregulin-1ß isoform, glial growth factor 2 (GGF2; USAN/INN; also called cimaglermin) were investigated in vitro. Various dosing regimens were then evaluated for their effects on left ventricular (LV) function in rats with surgically-induced myocardial infarction. In vitro, GGF2 bound with high affinity to erythroblastic leukemia viral oncogene (ErbB) 4 receptors, potently promoted Akt phosphorylation, as well as reduced cell death following doxorubicin exposure in HL1 cells. Daily GGF2 treatment beginning 7-14 days after left anterior descending coronary artery ligation produced improvements in LV ejection fraction and other measures of LV function and morphology. The improvements in LV function (e.g. 10% point increase in absolute LV ejection fraction) with GGF2 were dose-dependent. LV performance was substantially improved when GGF2 treatment was delivered infrequently, despite a serum half-life of less than 2h and could be maintained for more than 10 months with treatment once weekly or once every 2 weeks. These studies confirm previous findings that GGF2 may improve contractile performance in the failing rat heart and that infrequent exposure to GGF2 may improve LV function and impact remodeling in the failing myocardium. GGF2 is now being developed for the treatment of heart failure in humans.


Subject(s)
Heart Ventricles/drug effects , Myocardial Infarction/physiopathology , Neuregulin-1/pharmacology , Ventricular Dysfunction/drug therapy , Amino Acid Sequence , Animals , CHO Cells , Cricetinae , Cricetulus , Cytoprotection/drug effects , Doxorubicin/adverse effects , Drug Administration Schedule , Heart Failure/complications , Humans , Mice , Myocardial Infarction/complications , Neuregulin-1/administration & dosage , Neuregulin-1/chemistry , Neuregulin-1/metabolism , Rats , Receptor, ErbB-4/metabolism
5.
J Neurotrauma ; 34(3): 685-694, 2017 02.
Article in English | MEDLINE | ID: mdl-27503053

ABSTRACT

Magnesium (Mg2+) homeostasis is impaired following spinal cord injury (SCI) and the loss of extracellular Mg2+ contributes to secondary injury by various mechanisms, including glutamate neurotoxicity. The neuroprotective effects of high dose Mg2+ supplementation have been reported in many animal models. Recent studies found that lower Mg2+ doses also improved neurologic outcomes when Mg2+ was formulated with polyethylene glycol (PEG), suggesting that a PEG/ Mg2+ formulation might increase Mg2+ delivery to the injured spinal cord, compared with that of MgSO4 alone. Here, we assessed spinal extracellular Mg2+ and glutamate levels following SCI in rats using microdialysis. Basal levels of extracellular Mg2+ (∼0.5 mM) were significantly reduced to 0.15 mM in the core and 0.12 mM in the rostral peri-lesion area after SCI. A single intravenous infusion of saline or of MgSO4 at 192 µmoL/kg did not significantly change extracellular Mg2+ concentrations. However, a single infusion of AC105 (a MgCl2 in PEG) at an equimolar Mg2+ dose significantly increased the Mg2+ concentration to 0.3 mM (core area) and 0.25 mM (rostral peri-lesion area). Moreover, multiple AC105 treatments completely restored the depleted extracellular Mg2+ concentrations after SCI to levels in the uninjured spinal cord. Repeated MgSO4 infusions slightly increased the Mg2+ concentrations while saline infusion had no effect. In addition, AC105 treatment significantly reduced extracellular glutamate levels in the lesion center after SCI. These results indicate that intravenous infusion of PEG-formulated Mg2+ normalized the Mg2+ homeostasis following SCI and reduced potentially neurotoxic glutamate levels, consistent with a neuroprotective mechanism of blocking excitotoxicity.


Subject(s)
Drug Delivery Systems/methods , Extracellular Fluid/metabolism , Glutamic Acid/metabolism , Magnesium Sulfate/administration & dosage , Polyethylene Glycols/administration & dosage , Spinal Cord Injuries/metabolism , Animals , Excitatory Amino Acid Agonists , Extracellular Fluid/drug effects , Female , Infusions, Intravenous , Magnesium Sulfate/metabolism , Microdialysis/methods , Polyethylene Glycols/metabolism , Rats , Rats, Long-Evans , Spinal Cord Injuries/drug therapy , Thoracic Vertebrae
6.
J Neurotrauma ; 33(24): 2202-2216, 2016 12 15.
Article in English | MEDLINE | ID: mdl-27125815

ABSTRACT

A porcine model of spinal cord injury (SCI) was used to evaluate the neuroprotective effects of magnesium chloride (MgCl2) within a polyethylene glycol (PEG) formulation, called "AC105" (Acorda Therapeutics Inc., Ardsley, NY). Specifically, we tested the hypothesis that AC105 would lead to greater tissue sparing at the injury site and improved behavioral outcome when delivered in a clinically realistic time window post-injury. Four hours after contusion/compression injury, Yucatan minipigs were randomized to receive a 30-min intravenous infusion of AC105, magnesium sulfate (MgSO4), or saline. Animals received 4 additional infusions of the same dose at 6-h intervals. Behavioral recovery was tested for 12 weeks using two-dimensional (2D) kinematics during weight-supported treadmill walking and the Porcine Injury Behavior Scale (PTIBS), a 10-point locomotion scale. Spinal cords were evaluated ex vivo by diffusion-weighted magnetic resonance imaging (MRI) and subjected to histological analysis. Treatment with AC105 or MgSO4 did not result in improvements in locomotor recovery on the PTIBS or in 2D kinematics on weight-supported treadmill walking. Diffusion weighted imaging (DWI) showed severe loss of tissue integrity at the impact site, with decreased fractional anisotropy and increased mean diffusivity; this was not improved with AC105 or MgSO4 treatment. Histological analysis revealed no significant increase in gray or white matter sparing with AC105 or MgSO4 treatment. Finally, AC105 did not result in higher Mg2+ levels in CSF than with the use of standard MgSO4. In summary, when testing AC105 in a porcine model of SCI, we were unable to reproduce the promising therapeutic benefits observed previously in less-severe rodent models of SCI.


Subject(s)
Disease Models, Animal , Magnesium Chloride/administration & dosage , Polyethylene Glycols/administration & dosage , Spinal Cord Injuries/diagnostic imaging , Spinal Cord Injuries/prevention & control , Acute Disease , Animals , Drug Compounding , Drug Evaluation, Preclinical/methods , Female , Locomotion/drug effects , Locomotion/physiology , Magnesium Chloride/chemistry , Polyethylene Glycols/chemistry , Random Allocation , Recovery of Function/drug effects , Recovery of Function/physiology , Spinal Cord Injuries/physiopathology , Swine , Swine, Miniature , Thoracic Vertebrae
7.
J Neurosci Res ; 94(3): 253-65, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26660233

ABSTRACT

Cimaglermin (neuregulin 1ß3, glial growth factor 2) is a neuregulin growth factor family member in clinical development for chronic heart failure. Previously, in a permanent middle cerebral artery occlusion (pMCAO) rat stroke model, systemic cimaglermin treatment initiated up to 7 days after ischemia onset promoted recovery without reduced lesion volume. Presented here to extend the evidence are two studies that use a rat stroke model to evaluate the effects of cimaglermin dose level and dose frequency initiated 24 hr after pMCAO. Forelimb- and hindlimb-placing scores (proprioceptive behavioral tests), body-swing symmetry, and infarct volume were compared between treatment groups (n = 12/group). Possible mechanisms underlying cimaglermin-mediated neurologic recovery were examined through axonal growth and synapse formation histological markers. Cimaglermin was evaluated over a wider dose range (0.02, 0.1, or 1.0 mg/kg) than doses previously shown to be effective but used the same dosing regimen (2 weeks of daily intravenous administration, then 1 week without treatment). The dose-frequency study used the dose-ranging study's most effective dose (1.0 mg/kg) to compare daily, once per week, and twice per week dosing for 3 weeks (then 1 week without treatment). Dose- and frequency-dependent functional improvements were observed with cimaglermin without reduced lesion volume. Cimaglermin treatment significantly increased growth-associated protein 43 expression in both hemispheres (particularly somatosensory and motor cortices) and also increased synaptophysin expression. These data indicate that cimaglermin enhances recovery after stroke. Immunohistochemical changes were consistent with axonal sprouting and synapse formation but not acute neuroprotection. Cimaglermin represents a potential clinical development candidate for ischemic stroke treatment.


Subject(s)
Gene Expression Regulation/drug effects , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/physiopathology , Nerve Tissue Proteins/metabolism , Neuregulin-1/therapeutic use , Recovery of Function/drug effects , Analysis of Variance , Animals , Brain Infarction/drug therapy , Brain Infarction/etiology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Male , Rats , Rats, Sprague-Dawley , Time Factors
8.
Stroke ; 44(7): 1942-50, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23652269

ABSTRACT

BACKGROUND AND PURPOSE: Stroke survivors often have permanent deficits that are only partially addressed by physical therapy. This study evaluated the effects of dalfampridine, a potassium channel blocker, on persistent sensorimotor deficits in rats with treatment initiated 4 or 8 weeks after stroke. METHODS: Rats underwent permanent middle cerebral artery occlusion. Sensorimotor function was measured using limb-placing and body-swing symmetry tests, which normally show a partial recovery from initial deficits that plateaus ≈4 weeks after permanent middle cerebral artery occlusion. Dalfampridine was administered starting at 4 or 8 weeks after permanent middle cerebral artery occlusion in 2 blinded, vehicle-controlled studies. Plasma samples were collected and brain tissue was processed for histologic assessment. RESULTS: Dalfampridine treatment (0.5-2.0 mg/kg) improved forelimb- and hindlimb-placing responses and body-swing symmetry in a reversible and dose-dependent manner. Plasma dalfampridine concentrations correlated with dose. Brain infarct volumes showed no differences between treatment groups. CONCLUSIONS: Dalfampridine improves sensorimotor function in the rat permanent middle cerebral artery occlusion model. Dalfampridine extended-release tablets (prolonged release fampridine outside the United States) are used to improve walking in patients with multiple sclerosis, and these preclinical data provide a strong rationale for examining the potential of dalfampridine to treat chronic stable deficits in stroke patients. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01605825.


Subject(s)
4-Aminopyridine/therapeutic use , Disease Models, Animal , Infarction, Middle Cerebral Artery/drug therapy , Potassium Channel Blockers/pharmacology , Psychomotor Performance/drug effects , 4-Aminopyridine/administration & dosage , Animals , Cross-Over Studies , Dose-Response Relationship, Drug , Infarction, Middle Cerebral Artery/blood , Infarction, Middle Cerebral Artery/physiopathology , Male , Potassium Channel Blockers/administration & dosage , Rats , Rats, Sprague-Dawley , Time Factors
9.
Neuropharmacology ; 59(7-8): 640-9, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20691195

ABSTRACT

Neuregulins are a family of growth factors essential for normal cardiac and nervous system development. The EGF-like domain of neuregulins contains the active site which binds and activates signaling cascades through ErbB receptors. A neuregulin-1 gene EGF-like fragment demonstrated neuroprotection in the transient middle cerebral artery occlusion (MCAO) stroke model and drastically reduced infarct volume (Xu et al., 2004). Here we use a permanent MCAO rat model to initially compare two products of the neuregulin-1 gene and also assess levels of recovery with acute versus delayed time to treatment. In the initial study full-length glial growth factor 2 (GGF2) and an EGF-like domain fragment were compared with acute intravenous delivery. In a second study GGF2 only was delivered starting at 24h, 3 days or 7 days after permanent ischemia was induced. In both studies daily intravenous administration continued for 10 days. Recovery of neurological function was assessed using limb placing and body swing tests. GGF2 had similar functional improvements compared to the EGF-like domain fragment at equimolar doses, and a higher dose of GGF2 demonstrated more robust functional improvements compared to a lower dose. GGF2 improved sensorimotor recovery with all treatment paradigms, even enhancing recovery of function with a delay of 7 days to treatment. Histological assessments did not show any associated reduction in infarct volume at either 48 h or 21 days post-ischemic event. Neurorestorative effects of this kind are of great potential clinical importance, given the difficulty of delivering neuroprotective therapies within a short time after an ischemic event in human patients. If confirmed by additional work including additional data on mechanism(s) of improved outcome with verification in other stroke models, one can make a compelling case to bring GGF2 to clinical trials as a neurorestorative approach to improving outcome following stroke injury.


Subject(s)
Ischemic Attack, Transient/drug therapy , Neuregulin-1/therapeutic use , Neuroprotective Agents/therapeutic use , Stroke/drug therapy , Animals , Brain/drug effects , Brain/pathology , Brain Infarction/drug therapy , Brain Infarction/pathology , Epidermal Growth Factor/genetics , Humans , Ischemic Attack, Transient/pathology , Ischemic Attack, Transient/physiopathology , Male , Neuregulin-1/genetics , Protein Structure, Tertiary , Rats , Rats, Sprague-Dawley , Recombinant Proteins/genetics , Recombinant Proteins/therapeutic use , Stroke/pathology , Stroke/physiopathology , Time Factors
10.
J Neurotrauma ; 24(11): 1743-59, 2007 Nov.
Article in English | MEDLINE | ID: mdl-18001203

ABSTRACT

Chondroitinase treatment of experimental spinal cord injury improves recovery of sensory, motor, and autonomic functions. Chondroitinase catalyzes the cleavage of glycosaminoglycans (GAGs) from the core proteins of chondroitin sulfate proteoglycans (CSPGs). Little is known about changes in production of these proteoglycans in the clinically relevant contusion model of spinal cord injury or if CSPG content is altered by chondroitinase treatment. Female Long-Evans rats were injured with a forceps contusion injury and treated on alternate days with chondroitinase ABCI or control enzyme via an intrathecal catheter. Spinal cords were analyzed at specific times after injury. The cord was divided in 4 mm long segments, one containing the lesion, two rostral and two caudal to the lesion. These segments were assessed for CSPG protein and message content (NG2, neurocan and phosphacan) by Western blotting and real-time PCR. CSPG protein content was increased by one day post injury for all CSPGs investigated, and was increased in all segments examined rostral and caudal to the lesion site. Significant increases in CSPG were observed with peak content detected at 7, 7 and 14 days post injury for NG2, neurocan and phosphacan, respectively. Chondroitinase treatment had little impact upon the CPSG protein content. Changes in message levels of these CSPGs are also reported. This demonstrates that expression patterns of CSPGs in contusion injury are similar to those surrounding surgical hemisection lesions and demonstrates that the sensory and motor function enhancing effects of chondroitinase are likely due to removal of GAG chains rather than reduction in CSPG content.


Subject(s)
Chondroitin ABC Lyase/therapeutic use , Chondroitin Sulfate Proteoglycans/metabolism , Contusions/drug therapy , Contusions/metabolism , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/metabolism , Animals , Chondroitin Sulfate Proteoglycans/genetics , Female , RNA, Messenger/metabolism , Rats , Rats, Long-Evans , Reverse Transcriptase Polymerase Chain Reaction , Thoracic Vertebrae , Time Factors
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