Graft-tunnel motion may impair early graft incorporation and may lead to osteoclast-mediated bone resorption, contributing to tunnel widening. Early, aggressive postoperative rehabilitation may have detrimental effects on graft-to-bone healing.
The involvement of adenosine on the development of time-dependent reversal of long-term potentiation (LTP) by low-frequency stimulation (LFS) was investigated at Schaffer collateral-CA1 synapses of rat hippocampal slices. A train of LFS (2 Hz, 10 min, 1200 pulses) had no long-term effects on synaptic transmission but produced lasting depression of previously potentiated responses. This reversal of LTP (depotentiation) was observed when the stimulus was delivered
Macrophage depletion following anterior cruciate ligament reconstruction resulted in significantly improved morphologic and biomechanical properties at the healing tendon-bone interface, which we hypothesize are due to diminished macrophage-induced TGF-beta production.
Reversal of long term potentiation (LTP) may function to increase the flexibility and storage capacity of neuronal circuits; however, the underlying mechanisms remain incompletely understood. We show that depotentiation induced by low frequency stimulation (LFS) (2 Hz, 10 min, 1200 pulses) was input-specific and dependent on Nmethyl-D-aspartate (NMDA) receptor activation. The ability of LFS to reverse LTP was mimicked by a brief application of NMDA. This NMDA-induced depotentiation was blocked by adenosine A 1 receptor antagonist. However, the reversal of LTP by LFS was unaffected by metabotropic glutamate receptor antagonism. This LFS-induced depotentiation was specifically prevented by protein phosphatase (PP)1 inhibitors, okadaic acid, and calyculin A but not by the PP2A or PP2B inhibitors. Furthermore, by using phosphorylation site-specific antibodies, we found that LFS-induced depotentiation is associated with a persistent dephosphorylation of the GluR1 subunit of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor at serine 831, a protein kinase C and calcium/ calmodulin-dependent protein kinase II (CaMKII) substrate, but not at serine 845, a substrate of cAMPdependent protein kinase. This effect was mimicked by bath-applied adenosine or NMDA and was specifically prevented by okadaic acid. Also, the increased phosphorylation of CaMKII at threonine 286 and the decreased PP activity seen with LTP were overcome by LFS, adenosine, or NMDA application. These results suggest that LFS erases LTP through an NMDA receptor-mediated activation of PP1 to dephosphorylate amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and CaMKII in the CA1 region of the hippocampus. Long term potentiation (LTP)1 is a long lasting form of synaptic plasticity that is thought to play important roles in learning and memory in the brain (1). Although LTP is very persistent, current work has provided evidence that various manipulations or pharmacological treatment when applied shortly after LTP induction can reverse it. For example, it has been shown that transient anoxia occurring 1-2 min after LTP induction prevented the stable expression of LTP (2). Such time-dependent reversal of LTP was also effectively induced by low frequency afferent stimulation (1-5 Hz) when delivered within 10 min of LTP induction, both in vivo (3, 4) and in vitro (5-7). In addition, antagonists that prevent cell-cell and cellmatrix interactions were also observed to reverse effectively LTP in a time-dependent manner (8, 9). This reversal of synaptic strength from the potentiated state to pre-LTP levels has been called depotentiation and may provide a mechanism of preventing the saturation of synaptic potentiation and increase the efficiency and the capacity of the information storage of the neuronal networks (10). Although depotentiation has been consistently demonstrated in several brain regions including hippocampus (3-6, 11-14), visual cortex (15), sensorimotor cortex (16), and prefrontal cortex (17), the exact biochemical processes and mol...
Introduction Studies have demonstrated a significant decrease in skeletal mass, bone mineral density, and impaired fracture healing in the diabetic population. However, the effect of sustained hyperglycemia on tendon-to-bone healing is unknown. Materials and methods Forty-eight male, Lewis rats underwent unilateral detachment of the supraspinatus tendon followed by immediate anatomic repair with transosseous fixation. In the experimental group (n = 24), diabetes was induced preoperatively via intraperitoneal injection of streptozotocin (STZ, 65 mg/kg) and confirmed with both pre- and post-STZ injection intraperitoneal glucose tolerance tests (IPGTT). Animals were sacrificed at 1 and 2 weeks post-operatively for biomechanical, histomorphometric, and immunohistochemical analysis. Serum hemoglobin A1c (HbA1c) levels were measured at 2 weeks postoperatively. Statistical comparisons were performed using Student t tests with significance set at P < .05. Results IPGTT analysis demonstrated a significant impairment of glycemic control in the diabetic compared to control animals (P < .05). Mean HbA1c level at 2 weeks postoperatively was 10.6 ± 2.7% and 6.0 ± 1.0% for the diabetic and control groups, respectively (P < .05). Diabetic animals demonstrated significantly less fibrocartilage and organized collagen, and increased AGE deposition at the tendon-bone interface (P < .05). The healing enthesis of diabetic animals demonstrated a significantly reduced ultimate load-to-failure (4.79 ± 1.33N vs 1.60 ± 1.67N and 13.63 ± 2.33N vs 6.0 ± 3.24N for control versus diabetic animals at 1 and 2 weeks, respectively) and stiffness compared to control animals (P < .05). Discussion Sustained hyperglycemia impairs tendon-bone healing after rotator cuff repair in this rodent model. These findings have significant clinical implications for the expected outcomes of soft tissue repair or reconstructive procedures in diabetic patients with poor glycemic control. Level of Evidence Basic Science Study.
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