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1.
Horm Metab Res ; 46(6): 384-9, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24591047

ABSTRACT

Leptin is described as a pro-inflammatory signal in fat tissue, which is released from adipocytes and in turn activates immune cells. Also, leptin levels are known to be increased in pregnancies complicated with enhanced inflammatory processes in the placenta. Hence, we assumed that increased leptin amounts might contribute to inducing an inflammatory response in the placenta. To test this hypothesis, pregnant mice were continuously infused with recombinant murine leptin s. c. from day g13 to g16, resulting in a 3-fold increase of maternal circulating serum leptin levels. Dissected placentas were examined for the expression of pro-inflammatory cytokines IL-6 and TNF-alpha and the anti-inflammatory cytokine IL-10 using qPCR analysis. No changes were found except for TNF-alpha, which was slightly elevated upon leptin stimulation. However, TNF-alpha protein levels were not significantly higher in placentas from leptin treated mice. Also, leukocyte infiltration in the labyrinth section of placentas was not increased. In summary, our data demonstrate for the first time that elevated leptin levels alone do not induce an inflammatory response in the placenta.


Subject(s)
Inflammation/pathology , Leptin/metabolism , Placenta/metabolism , Placenta/pathology , Animals , Cytokines/metabolism , Feeding Behavior , Female , Inflammation/metabolism , Leukocytes/drug effects , Leukocytes/pathology , Matrix Metalloproteinase 9/metabolism , Mice, Inbred C57BL , Placenta/drug effects , Placenta/enzymology , Pregnancy , Suppressor of Cytokine Signaling 3 Protein , Suppressor of Cytokine Signaling Proteins/metabolism
2.
Restor Neurol Neurosci ; 30(5): 363-81, 2012.
Article in English | MEDLINE | ID: mdl-22695706

ABSTRACT

UNLABELLED: Following spinal cord injury (SCI), loss of spinal and supraspinal control results in desynchronisation of detrusor vesicae (parasympathicus) and external urethral sphincter (sympathicus) activity. Despite recovery of lower urinary tract function being a high priority in patients with SCI, effective treatment options are unavailable largely because mechanisms are poorly understood. PURPOSE AND METHODS: We used a clinically relevant model of thoracic SCI compression injury in adult female Wistar rats and confirmed that lesion volumes following severe injuries were significantly greater compared to moderate injuries (p < 0.05). Between 1-9 weeks, we assessed recovery of bladder function as well as return of locomotor function using the Basso, Beattie and Bresnahan (BBB) score. Bladder morphometrics and overall intramural innervation patterns, as assessed with ß-III tubulin immunohistochemistry, were also examined. RESULTS: Despite variability, bladder function was significantly worse following severe compared to moderate compression injury (p < 0.05); furthermore, the degree of bladder and locomotor dysfunction were significantly correlated (r = 0.59; p < 0.05). In addition, at 9 weeks after SCI we saw significantly greater increases in bladder dry weight (p < 0.05) and wall thickness following severe compared to moderate injury as well as increases in intramural axon density (moderate: 3× normal values; severe 5×; both p < 0.05) that also correlated with injury severity (r = 0.89). CONCLUSION: The moderate and severe compression models show consistent and correlated deficits in bladder and locomotor function, as well as in gross anatomical and histopathological changes. Increased intramural innervation may contribute to neurogenic detrusor overactivity and suggests the use of therapeutic agents which block visceromotoric efferents.


Subject(s)
Movement Disorders/etiology , Recovery of Function/physiology , Spinal Cord Compression/complications , Spinal Cord Compression/pathology , Urinary Bladder, Neurogenic/etiology , Animals , Disease Models, Animal , Female , Locomotion/physiology , Motor Activity/physiology , Nerve Fibers, Myelinated/pathology , Organ Size/physiology , Peripheral Nerves/pathology , Rats , Rats, Wistar , Regression Analysis , Severity of Illness Index , Time Factors , Tubulin/metabolism , Urinary Bladder/pathology , Urinary Bladder/physiopathology , Urinary Bladder, Neurogenic/pathology
3.
Neuroscience ; 182: 241-7, 2011 May 19.
Article in English | MEDLINE | ID: mdl-21440044

ABSTRACT

Functional recovery following facial nerve injury is poor. Adjacent neuromuscular junctions (NMJs) are "bridged" by terminal Schwann cells and numerous regenerating axonal sprouts. We have recently shown that manual stimulation (MS) restores whisking function and reduces polyinnervation of NMJs. Furthermore, MS requires both insulin-like growth factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF). Here, we investigated whether fibroblast growth factor-2 (FGF-2) was also required for the beneficial effects of MS. Following transection and suture of the facial nerve (facial-facial anastomisis, FFA) in homozygous mice lacking FGF-2 (FGF-2(-/-)), vibrissal motor performance and the percentage of poly-innervated NMJ were quantified. In intact FGF-2(-/-) mice and their wildtype (WT) counterparts, there were no differences in amplitude of vibrissal whisking (about 50°) or in the percentage of polyinnervated NMJ (0%). After 2 months FFA and handling alone (i.e. no MS), the amplitude of vibrissal whisking in WT-mice decreased to 22±3°. In the FGF-2(-/-) mice, the amplitude was reduced further to 15±4°, that is, function was significantly poorer. Functional deficits were mirrored by increased polyinnervation of NMJ in WT mice (40.33±2.16%) with polyinnervation being increased further in FGF-2(-/-) mice (50.33±4.33%). However, regardless of the genotype, MS increased vibrissal whisking amplitude (WT: 33.9°±7.7; FGF-2(-/-): 33.4°±8.1) and concomitantly reduced polyinnervation (WT: 33.9%±7.7; FGF-2(-/-): 33.4%±8.1) to a similar extent. We conclude that, whereas lack of FGF-2 leads to poor functional recovery and target reinnervation, MS can nevertheless confer some functional benefit in its absence.


Subject(s)
Facial Muscles/innervation , Facial Nerve Injuries/genetics , Facial Nerve Injuries/therapy , Fibroblast Growth Factor 2/deficiency , Musculoskeletal Manipulations/methods , Neuronal Plasticity/genetics , Recovery of Function/genetics , Animals , Disease Models, Animal , Facial Muscles/physiopathology , Facial Nerve Injuries/physiopathology , Fibroblast Growth Factor 2/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle Denervation/methods , Nerve Regeneration/genetics , Vibrissae/innervation
4.
Neuroscience ; 170(1): 372-80, 2010 Sep 29.
Article in English | MEDLINE | ID: mdl-20600640

ABSTRACT

Functional recovery following facial nerve injury is poor. Neuromuscular junctions (NMJs) are "bridged" by terminal Schwann cells and numerous regenerating axonal sprouts. We have shown that this poly-innervation of NMJs can be reduced by manual stimulation (MS) with restoration of whisking function. In addition, we have recently reported that insulin-like growth factor-1 (IGF-1) is required to mediate the beneficial effects of MS. Here we extend our findings to brain derived neurotrophic factor (BDNF). We then examined the effect of MS after facial-facial anastomosis (FFA) in heterozygous mice deficient in BDNF (BDNF(+/-)) or in its receptor TrkB (TrkB(+/-)). We quantified vibrissal motor performance and the percentage of NMJ bridged by S100-positive terminal Schwann cells. In intact BDNF(+/-) or TrkB(+/-) mice and their wild type (WT) littermates, there were no differences in vibrissal whisking nor in the percentage of bridged NMJ (0% in each genotype). After FFA and handling alone (i.e. no MS) in WT animals, vibrissal whisking amplitude was reduced (60% lower than intact) and the percentage of bridged NMJ increased (27% more than intact). MS improved both the amplitude of vibrissal whisking (not significantly different from intact) and the percentage of bridged NMJ (11% more than intact). After FFA and handling in BDNF(+/-) or TrkB(+/-) mice, whisking amplitude was again reduced (53% and 60% lower than intact) and proportion of bridged NMJ increased (24% and 29% more than intact). However, MS failed to improve outcome in both heterozygous strains (whisking amplitude 55% and 58% lower than intact; proportion of bridged NMJ 27% and 18% more than intact). We conclude that BDNF and TRkB are required to mediate the effects of MS on target muscle reinnervation and recovery of whisking function.


Subject(s)
Brain-Derived Neurotrophic Factor/physiology , Muscle Denervation , Nerve Regeneration/physiology , Receptor, trkB/physiology , Recovery of Function/physiology , Vibrissae/innervation , Vibrissae/physiology , Animals , Female , Mice , Mice, Transgenic , Physical Stimulation/methods , Random Allocation
5.
Exp Neurol ; 222(2): 226-34, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20067789

ABSTRACT

Recently, we showed that manual stimulation (MS) of denervated vibrissal muscles enhanced functional recovery following facial nerve cut and suture (FFA) by reducing poly-innervation at the neuro-muscular junctions (NMJ). Although the cellular correlates of poly-innervation are established, with terminal Schwann cells (TSC) processes attracting axon sprouts to "bridge" adjacent NMJ, molecular correlates are poorly understood. Since quantitative RT-PCR revealed a rapid increase of IGF-1 mRNA in denervated muscles, we examined the effect of daily MS for 2 months after FFA in IGF-1(+/-) heterozygous mice; controls were wild-type (WT) littermates including intact animals. We quantified vibrissal motor performance and the percentage of NMJ bridged by S100-positive TSC. There were no differences between intact WT and IGF-1(+/-) mice for vibrissal whisking amplitude (48 degrees and 49 degrees ) or the percentage of bridged NMJ (0%). After FFA and handling alone (i.e. no MS) in WT animals, vibrissal whisking amplitude was reduced (60% lower than intact) and the percentage of bridged NMJ increased (42% more than intact). MS improved both the amplitude of vibrissal whisking (not significantly different from intact) and the percentage of bridged NMJ (12% more than intact). After FFA and handling in IGF-1(+/-) mice, the pattern was similar (whisking amplitude 57% lower than intact; proportion of bridged NMJ 42% more than intact). However, MS did not improve outcome (whisking amplitude 47% lower than intact; proportion of bridged NMJ 40% more than intact). We conclude that IGF-I is required to mediate the effects of MS on target muscle reinnervation and recovery of whisking function.


Subject(s)
Facial Muscles/physiology , Facial Nerve Injuries/rehabilitation , Insulin-Like Growth Factor I/metabolism , Physical Stimulation/methods , Recovery of Function/physiology , Vibrissae/physiology , Analysis of Variance , Animals , Disease Models, Animal , Facial Nerve Injuries/pathology , Female , Functional Laterality/physiology , Gene Expression Regulation/physiology , Handling, Psychological , Insulin-Like Growth Factor I/deficiency , Mice , Mice, Knockout , Movement/physiology , Rats , Rats, Sprague-Dawley , Receptor, IGF Type 1/metabolism , Receptors, Nicotinic/metabolism , Regeneration/physiology , S100 Proteins/metabolism , Vibrissae/innervation
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