Expression of glutamate receptors and calcium-binding proteins in the retina of streptozotocin-induced diabetic rats

This study was aimed to investigate the expression of glutamate receptors and calcium-binding proteins in 1- and 4-month/s (mo) streptozotocin (STZ)-induced diabetic rats. Upregulation of glutamate receptors' [N-methyl-D-aspartate receptor (NMDAR)1 and GluR2/3] immunoreactivities was observed in the ganglion, amacrine and bipolar cells as well as in the inner and outer plexiform layers (IPL and OPL) in 1 mo diabetes and was further enhanced at 4 mo. Immunoreactivity of calcium-binding proteins (calbindin and parvalbumin) was also concomitantly increased. The present results suggest that upregulation of glutamate receptors and calcium-binding proteins may reflect changes of the glutamate and calcium metabolism in the diabetic retina. It is speculated that the above changes in the IPL and OPL may be linked to alteration of synaptic transmission in the diabetic retina.     

Modulation of heme oxygenase/carbon monoxide system affects the inhibitory neurotransmission involved in gastrointestinal motility of streptozotocin‐treated diabetic rats

Abstract Alterations in gastrointestinal motility of diabetic patients have been linked to degenerative changes induced by glucose abnormalities in the peripheral nervous system. The heme oxygenase/carbon monoxide (HO/CO) signalling represents one of the non‐adrenergic/non‐cholinergic (NANC) neurotransmission pathways involved in regulation of physiological peristalsis. To investigate the role of HO/CO system in intestinal motility under diabetic conditions, the response to electrical field stimulation (EFS) and western blot analysis of HO/CO pathway components were studied on duodenum longitudinal smooth muscle strips isolated from streptozotocin (STZ)‐treated diabetic rats (65 mg kg^?1, i.p.) and respective controls (CTRL), 6 weeks after the onset of diabetes. When compared to CTRL, the ability of CO releasing molecule (CORM‐3) (100–400 μmol L^?1) to enhance NANC relaxation was significantly impaired in STZ‐treated rats (P < 0.05). Conversely, in vitro incubation with the HO inhibitor ZnPPIX (10 μmol L^?1, 60 min) significantly reduced EFS‐induced relaxation in CTRL (P < 0.05), but not in STZ‐treated rats. Interestingly, the ability of ZnPPIX to inhibit EFS‐induced relaxation was partially restored in STZ‐treated rats co‐administered in vivo with the HO‐1 inducer cobalt protoporphyrin IX (CoPPIX) (0.5 mg per 100 g body weight weekly). Expression of inducible HO‐1 protein was increased in homogenates from STZ‐treated rats (vs CTRL, P < 0.01), and further increased in STZ‐treated rats receiving CoPPIX (P < 0.05). Taken together, our data underline the essential role of HO/CO system in regulation of inhibitory NANC neurotransmission in the duodenum and suggest that dysregulation of HO/CO activity may represent one mechanism by which gastrointestinal motility is altered in diabetes.     

Photoreceptor cell rescue at early and late RPE-cell transplantation periods during retinal disease in RCS dystrophic rats

Normal retinal pigment epithelial (RPE) cells were transplanted into retinas of Royal College of Surgeons (RCS) dystrophic rats at different stages of the retinal disease process. RPE-cell transplantation at 10, 17 and 26 days resulted in rescue of photoreceptor cells, such that at 4 months the outer nuclear layer (ONL) was 8-10 cells in thickness as shown in retinas of age-matched control rats. Of these transplantation times, day 17 appeared to affect the best rescue of photoreceptor cells. Nongrafted retinas of 4 month-old RCS dystrophic rats exhibited scattered PRC's, most prevalent in the peripheral retina. In addition, a small, but significant increase in the ONL thickness was detected in vehicle-injected retinas (sham control) of 17 day-old RCS dystrophic rats at 2 months; however, at 3 months, the ONL thickness was reduced to control levels. A normal distribution of (Na+ + K+)-ATPase immunostain was demonstrated beneath grafted RPE cells in retinas of 4 month-old RCS dystrophic rats. Dense immunostaining was shown along rescued photoreceptor cell inner segments (IS), within the inner (IPL) and outer (OPL) plexiform layers and on plasmalemma of cell bodies in the inner nuclear layer (INL). In nongrafted retinas of age-matched RCS dystrophic rats, immunostaining for (Na+ + K+)-ATPase was observed only in the INL and IPL. Under RPE-cells transplants in retinas of 4 month-old RCS dystrophic rats, opsin immunostaining was detected along both rescued photoreceptor cell inner and outer (OS) segments and on plasmalemma of ONL cell bodies. However, immunostaining for opsin was restricted to a debris zone in nongrafted retinas of age-matched RCS dystrophic rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Spinal Cord Stimulation on Peripheral Blood Circulation in Rats With Streptozotocin‐Induced Diabetes

Objective. The aim of this study was to investigate the effects of spinal cord stimulation (SCS) on peripheral circulation in rats with streptozotocin (STZ)‐induced diabetes. Materials and Methods. Four weeks after streptozotocin or vehicle was injected (i.p.) in male Sprague‐Dawley rats, SCS‐induced vasodilation was examined. Results. Plasma glucose concentration was significantly higher in diabetic rats than in the control animals. Motor threshold (MT) was significantly higher in diabetic rats than in control rats. SCS‐induced vasodilation was attenuated at 90% of the MT, but not at 30% and 60% of MT in diabetic rats when compared to control rats (p < 0.001, N = 13). Furthermore, increasing SCS from 30% to 90% of MT typically produced a progressive increase in blood flow in control rats but not in diabetic rats (p < 0.01, N = 13). Conclusion. This study suggested that SCS‐induced vasodilation improves peripheral blood flow, although the pathways were partially impaired in the diabetic condition.     

Cone synapses in mammalian retinal rod bipolar cells

Some mammalian rod bipolar cells (RBCs) can receive excitatory chemical synaptic inputs from both rods and cones (DBC_R2), but anatomical evidence for mammalian cone‐RBC contacts has been sparse. We examined anatomical cone‐RBC contacts using neurobiotin (NB) to visualize individual mouse cones and standard immuno‐markers to identify RBCs, cone pedicles and synapses in mouse and baboon retinas. Peanut agglutinin (PNA) stained the basal membrane of all cone pedicles, and mouse cones were positive for red/green (R/G)‐opsin, whereas baboon cones were positive for calbindin D‐28k. All synapses in the outer plexiform layer were labeled for synaptic vesicle protein 2 (SV2) and PSD (postsynaptic density)‐95, and those that coincided with PNA resided closest to bipolar cell somas. Cone‐RBC synaptic contacts were identified by: (a) RBC dendrites deeply invaginating into the center of cone pedicles (invaginating synapses), (b) RBC dendritic spines intruding into the surface of cone pedicles (superficial synapses), and (c) PKCα immunoreactivity coinciding with synaptic marker SV2, PSD‐95, mGluR6, G protein beta 5 or PNA at cone pedicles. One RBC could form 0‐1 invaginating and 1‐3 superficial contacts with cones. 20.7% and 38.9% of mouse RBCs contacted cones in the peripheral and central retina (p < .05, n = 14 samples), respectively, while 34.4% (peripheral) and 48.5% (central) of cones contacted RBCs (p > .05). In baboon retinas (n = 4 samples), cone‐RBC contacts involved 12.2% of RBCs (n = 416 cells) and 22.5% of cones (n = 225 cells). This suggests that rod and cone signals in the ON pathway are integrated in some RBCs before reaching AII amacrine cells.     

Impaired formation of the inner retina in an AChE knockout mouse results in degeneration of all photoreceptors

Blinding diseases can be assigned predominantly to genetic defects of the photoreceptor/pigmented epithelium complex. As an alternative, we show here for an acetylcholinesterase (AChE) knockout mouse that photoreceptor degeneration follows an impaired development of the inner retina. During the first 15 postnatal days of the AChE-/- retina, three major calretinin sublaminae of the inner plexiform layer (IPL) are disturbed. Thereby, processes of amacrine and ganglion cells diffusely criss-cross throughout the IPL. In contrast, parvalbumin cells present a nonlaminar IPL pattern in the wild-type, but in the AChE-/- mouse their processes become structured within two 'novel' sublaminae. During this early period, photoreceptors become arranged regularly and at a normal rate in the AChE-/- retina. However, during the following 75 days, first their outer segments, and then the entire photoreceptor layer completely degenerate by apoptosis. Eventually, cells of the inner retina also undergo apoptosis. As butyrylcholinesterase (BChE) is present at a normal level in the AChE-/- mouse, the observed effects must be solely due to the missing AChE. These are the first in vivo findings to show a decisive role for AChE in the formation of the inner retinal network, which, when absent, ultimately results in photoreceptor degeneration.     

Selective lectin binding of the developing mouse retina

A battery of eight lectins with different carbohydrate specificities was used to study changes in glycoconjugate expression during cell differentiation in the mouse retina. The lectins tested included concanavalin A (Con A), wheat germ agglutinin (WGA), soybean agglutinin (SBA), peanut agglutinin (PNA), Ulex europaeus agglutinin (UEA), Ricinus communis agglutinin I (RCA), Dolichos biflorus agglutinin (DBA), and Limulus polyphemus agglutinin (LPA). Unfixed frozen sections of adult and early postnatal mouse retina were treated with fluorescein isothiocyanate-conjugated lectins and examined by fluorescence microscopy. The results showed selective lectin binding in both cellular and synaptic retinal layers of the adult mouse and throughout postnatal development. In general, an increase in intensity of fluorescent lectin staining during retinal development was observed for Con A, WGA, DBA, LPA, RCA, and PNA. This suggests an increase in the expression or accessibility of carbohydrate moieties during development. SBA and UEA showed little to no binding to adult or neonatal retina. Retinal vasculature was intensely stained by RCA, both during development and in the adult. All lectins binding to adult or neonatal retinal layers showed some degree of reactivity with the inner segment region of photoreceptor cells. However, only Con A, PNA and WGA bound to photoreceptor outer segments, suggesting significant differences in the glycosylated components of inner and outer segment membranes. PNA bound specifically to a subpopulation of photoreceptor cells and to discrete regions within the outer synaptic layer. The pattern of PNA binding suggests that this lectin binds preferentially to cone photoreceptor inner and outer segments and cone synaptic pedicles rather than to rod photoreceptor cells. This marked specificity of PNA binding suggests that it may provide a basis for the physical separation of cone and rod photoreceptor cells.     

Celecoxib Alleviates Memory Deficits by Downregulation of COX-2 Expression and Upregulation of the BDNF-TrkB Signaling Pathway in a Diabetic Rat Model

Previous studies conveyed that diabetes causes learning and memory deficits. Data also suggest that celecoxib exerts an anti-hyperalgesic, anti-allodynic, and a plethora of other beneficial effects in diabetic rats. However, whether celecoxib could alleviate memory deficit in diabetic rat is unknown. In the present study, we aimed to examine the potential of celecoxib to counter memory deficits in diabetes. Experimental diabetes was induced by streptozotocin (STZ, 60 mg/kg) in male SD rats. Rats were divided into three groups (n = 16/group): normal control group injected with normal saline, diabetes group injected with STZ, and diabetes + celecoxib group in which diabetic rats were administered with celecoxib by gavage in drinking water (10 mg/kg) for 10 days in terms of which memory performance in animals was measured, hippocampal tissue harvested, and long-term potentiation assessed. Western blotting and immunohistochemical staining were performed to determine cyclooxygenase 2 (COX-2) expression in hippocampus. The results showed that a rat model of STZ-induced diabetes was successfully established and that celecoxib treatment significantly improved the associated nephropathy and inflammation. Moreover, spatial memory and hippocampal long-term potentiation (LTP) were impaired in diabetic model (P < 0.05). Interestingly, our data revealed that oral application of celecoxib reversed the memory deficit and hippocampal LTP in the diabetic rats. To understand the underlying mechanisms, the expression of some important pathways involved in memory impairment was determined. We found that brain-derived neurotrophic factor (BDNF) and phosphorylated tropomyosin-related kinase (p-TrkB) were decreased in diabetic rats but were effectively reversed by celecoxib treatment. As evidenced by western blotting and immunohistochemical staining, the expression of COX-2 in hippocampus was significantly upregulated in diabetic rat (P < 0.05) but inhibited by celecoxib treatment. The present findings provide novel data that celecoxib reverses memory deficits via probable downregulation of hippocampal COX-2 expression and upregulation of the BDNF-TrkB signaling pathway in a diabetic rat.     

Beta-adrenergic receptor regulation of pigment epithelial-derived factor expression in rat retina

In the present study, we have examined a potential mechanism by which sympathetic nerves regulate PEDF and whether its down regulation may be responsible for increased capillary density observed after sympathectomy. Six weeks post-sympathectomy, eyes were removed from female Sprague-Dawley rats for Western blot analysis, RNA isolation, real-time PCR, and immunohistochemistry for measurement of PEDF expression. The contralateral or left eye was used as an intra-animal control. In addition, retinal pigment epithelial cells were grown in culture and treated with norepinephrine and propranolol. An ELISA assay was used to determine the amount of PEDF secreted into the RPE media. Quantitative results of Western blot analysis and real-time PCR confirm that both steady-state gene expression and protein levels of PEDF are significantly decreased in the sympathectomized retina (P<0.05) when compared to the contralateral retina. Qualitative results of immunohistochemistry verify that PEDF is located predominantly in the RPE cell layer of the retina, and levels are decreased in the sympathectomized retina. ELISA results illustrate that norepinephrine significantly increases PEDF secretion by RPE cells and propranolol slightly decreases PEDF secretion into RPE cell medium. In conclusion, down regulation of PEDF may contribute to the increased capillary density of the outer plexiform layer in the retina noted after sympathectomy. Furthermore, expression of PEDF was significantly increased after treatment of norepinephrine in RPE medium demonstrating a role of beta-adrenergic regulation of PEDF. Since sympathetic nerves are damaged in diabetes and PEDF appears to be regulated by beta-adrenergic receptors, these results suggest a role for sympathetic nerves in diabetic retinopathy. This knowledge, in turn, may be used for future treatment and prevention of diabetic retinopathy and other ocular diseases.     

Expression of vesicular glutamate transporter 1 in the mouse retina reveals temporal ordering in development of rod vs. cone and ON vs. OFF circuits

Glutamatergic transmission is crucial to the segregation of ON and OFF pathways in the developing retina. The temporal sequence of maturation of vesicular glutamatergic transmission in rod and cone photoreceptor and ON and OFF bipolar cell terminals is currently unknown. Vesicular glutamate transporters (VGLUTs) that load glutamate into synaptic vesicles are necessary for vesicular glutamatergic transmission. To understand better the formation and maturation of glutamatergic transmission in the rod vs. cone and ON vs. OFF pathways of the retina, we examined the developmental expression of VGLUT1 and VGLUT2 immunocytochemically in the mouse retina. Photoreceptor and bipolar cell terminals showed only VGLUT1-immunoreactivity (-IR); no VGLUT2-IR was present in any synapses of the developing or adult retina. VGLUT1-IR was first detected in cone photoreceptor terminals at postnatal day 2 (P2), several days before initiation of ribbon synapse formation at P4-P5. Rod terminals showed VGLUT1-IR by P8, when they invade the outer plexiform layer (OPL) and initiate synaptogenesis. Developing OFF bipolar cell terminals showed VGLUT1-IR around P8, 2-3 days after bipolar terminals were first identified in the inner plexiform layer (IPL) by labeling for the photoreceptor and bipolar cell terminal marker, synaptic vesicle protein 2B. Although terminals of ON bipolar cells were present in the IPL by P6-P8, most did not show VGLUT1-IR until P8-P10 and increased dramatically from P12. These data suggest a hierarchical development of glutamatergic transmission in which cone circuits form prior to rod circuits in both the OPL and IPL, and OFF circuits form prior to ON circuits in the IPL.     

Naringenin neutralises oxidative stress and nerve growth factor discrepancy in experimental diabetic neuropathy

Abstract

Objectives:

Present study aims to investigate the ameliorative effects of naringenin (NG) on experimentally induced diabetic neuropathy (DN) in rats.

Methods:

Diabetes was induced by single intraperitoneal injection of streptozotocin (STZ, 60?mg/kg). Naringenin (25 and 50?mg/kg/day) treatment was started 2?weeks after the diabetes induction and continued for five consecutive weeks. Pain threshold behaviour tests were performed at the end of the treatment. Serum levels of glucose, insulin and pro-inflammatory cytokines were assessed. In sciatic tissues, markers oxidative stress, cytokines and neurotrophic factors were measured.

Results:

NG treatments showed significant decrease in paw-withdrawal (P?<?0.01) and tail-flick latency (P?<?0.01). The drug attenuated the diabetic-induced changes in serum glucose, insulin and pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6). In sciatic nerve, the diabetic-induced alterations in interleukins and oxidative stress biomarkers were significantly attenuated by NG. Decreased sciatic expressions of insulin growth factor (IGF) and nerve growth factor (NGF) in diabetic rats were also ameliorated by NG. Diabetes-induced dysregulated levels of nitric oxide (NO), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were ameliorated by NG. Histological analysis showed that NG corrected the altered sciatic changes in diabetic animals.

Discussion:

We suggest that neuro-protective effect of NG molecules in sciatic nerve of diabetic rats, through its anti-diabetic as well as antioxidant and anti-inflammatory properties.     

Visual Field Loss in RCS Rats and the Effect of RPE Cell Transplantation

The consequences of progressive retinal degeneration on central visual function were studied by recording single and multiunit receptive fields (RFs) across the surface of the superior colliculus (SC) of pigmented dystrophic RCS rats. Retinal morphology was used to provide a correlation between function and histological appearance. In addition, the potential protective effect of retinal pigment epithelium (RPE) transplantation was studied in a similar manner in dystrophic animals in which RPE cells were injected into the subretinal space, or the vitreous humor, at between 21 and 28 days of age. The visual responsiveness of SC units in dystrophic rats differed markedly from those in nondystrophics. Dystrophic rats developed a relative scotoma beginning in the central visual field by 42–45 days of age and expanding to include 50% of the visual field by 97–107 days. In contrast, following subretinal RPE transplantation, there was photoreceptor rescue correlated with a partial to complete preservation of RF representation when examined at 85 to 108 days of age. The majority of photoreceptor rescue occurred in the region of graft placement with possible low level rescue across the central retina. Dystrophic animals that had received intravitreal RPE transplants showed poor photoreceptor survival as well as minimal functional preservation. Our results indicate that there is a progressive central to peripheral loss of visual responsiveness in the SC of dystrophic RCS rats which can be limited by subretinal injections of healthy RPE cells.     

cGMP‐dependent cone photoreceptor degeneration in the cpfl1 mouse retina

Inherited retinal degeneration affecting both rod and cone photoreceptors constitutes one of the leading causes of blindness in the developed world. Such degeneration is at present untreatable, and the underlying neurodegenerative mechanisms are unknown, even though certain genetic causes have been established. The rd1 mouse is one of the best characterized animal models for rod photoreceptor degeneration, whereas the cpfl1 mouse is a recently discovered model for cone cell death. Because both animal models are affected by functionally similar mutations in the rod and cone phosphodiesterase 6 genes, respectively, we asked whether the mechanisms of photoreceptor degeneration in these two mouse lines share common pathways. In the present study, we followed the temporal progression of photoreceptor degeneration in the cpfl1 retina, correlated it with specific metabolic markers, and compared it with the wild‐type and the rd1 situation. Similar to corresponding rd1 observations, cpfl1 cone photoreceptor cell death was associated with an accumulation of cyclic guanosine monophosphate (cGMP), activity of calpains, and phosphorylation of vasodilator‐stimulated protein (VASP). Cone degeneration progressed rapidly, with a peak in cell death around postnatal day 24. Furthermore, cpfl1 cone photoreceptor migration during early postnatal development was delayed significantly compared with the corresponding wild‐type retina. The finding that rod and cone photoreceptor degeneration was associated with the same metabolic markers suggests that in both cell types similar degenerative mechanisms are active. This raises the possibility that equivalent neuroprotective strategies may be used to prevent both rod and cone photoreceptor degeneration. J. Comp. Neurol. 518:3604–3617, 2010. © 2010 Wiley‐Liss, Inc.     

Long‐term neuroplasticity of the face primary motor cortex and adjacent somatosensory cortex induced by tooth loss can be reversed following dental implant replacement in rats

Tooth loss is common, and exploring the neuroplastic capacity of the face primary motor cortex (face‐M1) and adjacent primary somatosensory cortex (face‐S1) is crucial for understanding how subjects adapt to tooth loss and their prosthetic replacement. The aim was to test if functional reorganization of jaw and tongue motor representations in the rat face‐M1 and face‐S1 occurs following tooth extraction, and if subsequent dental implant placement can reverse this neuroplasticity. Rats (n = 22) had the right maxillary molar teeth extracted under local and general anesthesia. One month later, seven rats had dental implant placement into healed extraction sites. Naive rats (n = 8) received no surgical treatment. Intracortical microstimulation (ICMS) and recording of evoked jaw and tongue electromyographic responses were used to define jaw and tongue motor representations at 1 month (n = 8) or 2 months (n = 7) postextraction, 1 month postimplant placement, and at 1–2 months in naive rats. There were no significant differences across study groups in the onset latencies of the ICMS‐evoked responses (P > 0.05), but in comparison with naive rats, tooth extraction caused a significant (P < 0.05) and sustained (1–2 months) decreased number of ICMS‐defined jaw and tongue sites within face‐M1 and ‐S1, and increased thresholds of ICMS‐evoked responses in these sites. Furthermore, dental implant placement reversed the extraction‐induced changes in face‐S1, and in face‐M1 the number of jaw sites even increased as compared to naive rats. These novel findings suggest that face‐M1 and adjacent face‐S1 may play a role in adaptive mechanisms related to tooth loss and their replacement with dental implants. J. Comp. Neurol. 523:2372–2389, 2015. © 2015 Wiley Periodicals, Inc.     

Repeated monitoring of corneal nerves by confocal microscopy as an index of peripheral neuropathy in type‐1 diabetic rodents and the effects of topical insulin

We developed a reliable imaging and quantitative analysis method for in vivo corneal confocal microscopy (CCM) in rodents and used it to determine whether models of type 1 diabetes replicate the depletion of corneal nerves reported in diabetic patients. Quantification was reproducible between observers and stable across repeated time points in two rat strains. Longitudinal studies were performed in normal and streptozotocin (STZ)‐diabetic rats, with innervation of plantar paw skin quantified using standard histological methods after 40 weeks of diabetes. Diabetic rats showed an initial increase, then a gradual reduction in occupancy of nerves in the sub‐basal plexus so that values were significantly lower at week 40 (68 ± 6%) than age‐matched controls (80 ± 2%). No significant loss of stromal or intra‐epidermal nerves was detected. In a separate study, insulin was applied daily to the eye of control and STZ‐diabetic mice and this treatment prevented depletion of nerves of the sub‐basal plexus. Longitudinal studies are viable in rodents using CCM and depletion of distal corneal nerves precedes detectable loss of epidermal nerves in the foot, suggesting that diabetic neuropathy is not length dependent. Loss of insulin‐derived neurotrophic support may contribute to the pathogenesis of corneal nerve depletion in type 1 diabetes.     

Phototoxic-induced photoreceptor degeneration causes retinal ganglion cell degeneration in pigmented rats

Human retinitis pigmentosa results eventually in retinal ganglion cell (RGC) death, but how this occurs remains obscure. We have previously documented that in pigmented dystrophic Royal College of Surgeons (RCS) rats, photoreceptor degeneration is followed by retinal pigment epithelial (RPE) migration, formation of RPE-vascular complexes, and vascular displacement that causes RGC axonal compression and death. To investigate if phototoxic-induced photoreceptor degeneration is capable of causing similar pathologic events, we dilated the left pupil of pigmented nondystrophic RCS and Lister-Hooded rats and exposed them to light (3000 lux) for 72 hours. After various survival periods ranging between 0 hours and 21 months, the retinas were processed as whole mounts or in cross-sections. Two separate retinal degenerative events that may relate to differential light exposure across the retina were observed: an early arciform area of degeneration in the superotemporal retina and a delayed degeneration in the central and ventral retina. Although degeneration in the arciform area was always more severe and developed earlier (sensitive region), both of them showed quite comparable pathologic events to those described for dystrophic RCS rats. RGC axonal compression was seen as soon as 21 days after light exposure and RGC loss was seen 9 months after light exposure, mainly in the superotemporal retina, but also in the ventral retina. The results show that RGC loss in induced photoreceptor degeneration results from a similar series of events to those occurring as a consequence of inherited degeneration and therefore is not uniquely a property of inherited photoreceptor degeneration.     

Oral corticosteroid therapy and present disease status in myasthenia gravis

Introduction: The aim of this study was to elucidate the effectiveness of oral prednisolone (PSL) according to dosing regimen in 472 patients with myasthenia gravis (MG). Methods: We compared the clinical characteristics and PSL treatment between 226 patients who achieved minimal manifestations (MM) or better and 246 patients who remained improved (I) or worsened, according to the MG Foundation of America postintervention status. Results: Achievement of MM or better at peak PSL dose (odds ratio 12.25, P < 0.0001) and combined use of plasma exchange/plasmapheresis (PE/PP) and/or intravenous immunoglobulin (IVIg) (odds ratio 1.92, P = 0.04) were associated positively, and total PSL dose during the past year (odds ratio 0.17, P = 0.03) was associated negatively with present MM or better status. Conclusions: Higher PSL dose and longer PSL treatment do not ensure better outcome. In the absence of a good response, the PSL dose should be decreased by combining with modalities such as PE/PP or IVIg. Muscle Nerve 51 :692–696, 2015     

Perineurial abnormalities in the spontaneously diabetic dog

Structural abnormalities of the perineurium from six spontaneously diabetic dogs (diabetes duration 4–8 years and six control animals were quantified using detailed electron microscopic morphometric methods on superficial peroneal nerve biopsy specimens. Total perineurial sheath thickness (μm) was significantly increased in diabetic (8.8 ± 0.6) compared to control animals (6.2 ± 0.3) (P < 0.02). This was attributed to a significant increase in the mean perineurial lamellar width in diabetic (0.49 ± 0.03) compared to control (0.40 ± 0.01) (P < 0.04) animals. The number of lamellae also showed a non-significant increase in diabetic animals (7.8 ± 0.4) compared to controls (6.9 ± 0.13) (P < 0.06). There was no change in the mean interlamellar space in diabetic (0.7 ± 0.05) compared to control (0.6 ± 0.06) (P = 0.15) animals. The total interlamellar space was increased in diabetic (5.7 ± 0.5) compared to control (4.1 ± 0.36) (P < 0.04) animals. The perineurial cell basement membrane thickness (nm) was significantly increased in diabetic (126.9 ± 9.8) compared to control (62.8 ± 6.1) (P < 0.005) animals. The current study has demonstrated significant abnormalities of the perineurium in the spontaneously diabetic dog, which may have relevance to the pathogenesis of diabetic neuropathy. Received: 12 May 1998 / Revised: 16 July 1998 / Accepted: 23 July 1998     

Expression of neuropeptides in experimental diabetes; effects of treatment with nerve growth factor or brain-derived neurotrophic factor

Rats with streptozotocin-induced diabetes of 4 to 6 weeks duration showed a depletion of both substance P (P < 0.01) and calcitonin gene-related peptide (P < 0.01) in the sciatic nerve. Since expression of both peptides is sensitive to nerve growth factor (NGF) in vitro we examined the effect of treatment of diabetic rats with NGF, which significantly increased the levels of both peptides in treated diabetic animals (P < 0.01 for both). Treatment of non-diabetic rats with a similar NGF regime raised the mean peptide levels to a value similar to that seen in treated diabetic rats but the change was not statistically significant. In vehicle-treated diabetic rats the depletions of sciatic nerve neuropeptides were accompanied by a significant (P < 0.05) reduction in the level of CGRP mRNA in the 4th and 5th lumbar dorsal root ganglia, this was accompanied by an analogous reduction in the mRNA for γ-preprotachykinin A (γ-PPT), which did not attain statistical significance. Treatment of diabetic rats with NGF also prevented the deficits in the levels of CGRP and γ-PPT mRNA in the lumbar dorsal root ganglia (P < 0.05). Treatment of other diabetic rats with the related neurotrophin, brain-derived neurotrophic factor (BDNF), had no effect on the levels of substance P and calcitonin gene-related peptide in the sciatic nerve.