Biomedical subjects

Kwok-Fai So

Publications and source records attributed to Kwok-Fai So.

At least 19 recordsLinked to original sources

PubMed2006

Neuroprotective effects of Lycium barbarum Lynn on protecting retinal ganglion cells in an ocular hypertension model of glaucoma.

Glaucoma is one of the major neurological disorders in eye leading to irreversible blindness in elderly. Increase in intraocular pressure (IOP) has been considered to be the major risk factor for the progressive loss of retinal ganglion cells (RGCs) in retina. While attenuation of IOP has been a major pharmaceutical target, reduction of IOP cannot prevent progressive loss of RGCs. In this regard, urgent need for alternative treatment has to be investigated. Anti-aging medicinal herb Lycium barbarum L. has been used for centuries in Eastern World to protect the eyes and maintain good health. Using an ocular hypertension (OH) model in rat by laser photocoagulation of episcleral and limbal veins, we attempted to investigate whether L. barbarum can promote RGCs survival against elevated IOP. Oral administration of L. barbarum in Sprague-Dawley rats (250-280 g) significantly reduced the loss of RGCs, although elevated IOP was not significantly altered. Rats fed with the 1 mg/kg extract could nearly totally escape from pressure-induced loss of RGCs. In conclusion, this is the first in vivo report showing the therapeutic function of L. barbarum against neurodegeneration in the retina of rat OH model. The results demonstrate that this extract may be a potential candidate for the development of neuroprotective drug against the loss of RGCs in glaucoma.

Administration, Oral↗

PubMed2006

A suprachiasmatic nucleus projecting retinal ganglion cell exhibits an unusually large dendritic field in the hamster.

The majority of retinal ganglion cells innervating the suprachiasmatic nucleus are intrinsically light sensitive, while the rest are conventional ganglion cells that collect inputs through conventional photoreceptors. Here we report a rarely encountered ganglion cell that had a dendritic field covering approximately 14.4% of retinal surface and its processes ramified in both the inner and the outer plexiform layers. This cell could have a potential role in detecting luminance changes over a large area of retinal surface.

Animals↗

PubMed2006

LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury.

LINGO-1 is a CNS-specific protein and a functional component of the NgR1/p75/LINGO-1 and NgR1/TAJ(TROY)/LINGO-1 signaling complexes that mediate inhibition of axonal outgrowth. These receptor complexes mediate the axonal growth inhibitory effects of Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp) via RhoA activation. Soluble LINGO-1 (LINGO-1-Fc), which acts as an antagonist of these pathways by blocking LINGO-1 binding to NgR1, was administered to rats after dorsal or lateral hemisection of the spinal cord. LINGO-1-Fc treatment significantly improved functional recovery, promoted axonal sprouting and decreased RhoA activation and increased oligodendrocyte and neuronal survival after either rubrospinal or corticospinal tract transection. These experiments demonstrate an important role for LINGO-1 in modulating axonal outgrowth in vivo and that treatment with LINGO-1-Fc can significantly enhance recovery after spinal cord injury.

Analysis of Variance↗

PubMed2006

The response of magnocellular neurons of the hypothalamo-neurohyphyseal system to hypophysectomy, nitric oxide synthase expression as well as survival and regeneration in developing vs. adult rats.

This study examined the age-related changes in nitric oxide synthase immunoreactivity (NOS-IR), survival and regeneration of magnocellular neurons in the hypothalamo-neurohypophyseal system (HNS) in rats following hypophysectomy. In adult animal, hypophysectomy induced a significant increase in NOS-IR in the supraoptic (SON), paraventricular nuclei (PVN) and median eminence (ME) by 3 days post-lesion. NOS sustained an increased level until 2 weeks after hypophysectomy and then returned to normal control level. In contrast, at postnatal day 7 (PN7), no obvious increase in NOS-IR was observed in the SON, PVN and ME following the injury compared with age-matched controls. At PN14, the same injury induced an increase in NOS-IR in SON, PVN and ME but the increase was more transient with peak NOS-IR at 3 days and returning to the corresponding control level at 1 week after hypophysectomy. In contrast to a striking age-dependent alteration in NOS-IR in the SON and PVN, hypophysectomy induced substantial degeneration of arginine vasopressin (AVP) and oxytocin (OT) neurons in the SON and PVN in both immature and adult rats and there was no obvious difference in neuronal survival after the same injury among these three groups of different ages by quantitative analysis. Following hypophysectomy, a large number of fibers were observed in the contact zone of the median eminence and the adjacent lumen of the third cerebral ventricle (V3) in adult rats, whereas few fibers could be found in the lumen of the V3 in the immature rats after the same injury. Relationships between NOS induction and magnocellular neuronal survival and regeneration were discussed.

Age Factors↗

PubMed2006

Graded ephrin-A2 expression in the developing hamster superior colliculus.

During development, ephrin gradients guide retinal ganglion cell axons to their appropriate topographic locations in the superior colliculus (SC). Expression of ephrin-A2, assessed immunohistochemically in the developing hamster SC, revealed a rostral(low) to caudal (high) gradient that is most prominent at postnatal days P4 and P7 when topography is established. Double-labelling immunohistochemistry for ephrin-A2 and cell specific markers revealed that ephrin-A2 is expressed exclusively by a subset of neurons. The expression pattern has implications for mechanisms underlying establishment of topography during development and following injury.

Animals↗

PubMed2006

Expression of nicotinamide adenine dinucleotide phosphate-diaphorase in the retina of postnatal golden hamsters deprived of light stimulation.

Nicotinamide Adenine Dinucleotide Phosphate-Diaphorase (NADPH-d) expressing neurons in the retina of golden hamsters have been identified to be a subset of amacrine cells that provide a major source of Nitric Oxide (NO) in retina. This subset of amacrine cells in mouse retina was recently proved to contain the circadian clock gene Per1 (D.Q. Zhang, T. Zhou, G.X. Ruan, D.G. McMahon, Circadian rhythm of Period 1 clock gene expression in NOS amacrine cells of the mouse retina, Brain Res., 1050 (2005) 101-109). However, it remains unknown whether these clock-related NADPH-d amacrine cells can be regulated by light stimulation and thus synchronized to ambient day/night cycle. A previous study has reported that NADPH-d expressing amacrine cells in postnatal hamsters exhibited a surge after eye-opening (D. Tay, Y.C. Diao, Y.M. Xiao, K.F. So, Postnatal development of nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons in the retina of the golden hamster, J. Comp. Neurol., 446 (2002) 342-348) suggesting a possible effect of light on the NADPH-d amacrine cells. In order to further reveal the relationship between NADPH-d amacrine cells and light stimulation, the present study focuses on the changes of the expression of NADPH-d in the retina of postnatal hamsters reared in completely deprived light conditions. Prior to eye opening, P12 hamster pups were subjected to either bilateral eyelid suturing or dark rearing. On P28 a subgroup of light deprived hamsters was returned to lighting conditions and the expression of NADPH-d activities in the retina was assessed. In hamsters reared in the 12:12 light-dark cycle, the number of NADPH-d amacrine cells in the ganglion cell layer (GCL) increased right after eye-opening and reached the adult level gradually. However, hamsters subjected to both bilateral eyelid suturing and dark rearing, the number of NADPH-d amacrine cells in GCL was maintained at a low level but increased again upon returning to the 12:12 light-dark condition. In contrast, the number of NADPH-d expressing amacrine cells in the inner nuclear layer (INL) remained low and unaltered regardless of the lighting environment. This study demonstrates that there are two subpopulations of NADPH-d expressing amacrine cells with respect to different locations in the retina of hamsters. Different from those in INL, the NADPH-d amacrine cells in GCL of postnatal hamsters are dependent on the lighting environment implicating that these clock-related amacrine cells and the production of NO might be under a modulation of light stimulation.

Animals↗

PubMed2006

Age-related reexpression of p75 in axotomized motoneurons.

p75 was immunohistochemically identified in spinal motoneurons in immature and adult rats after either distal peripheral axotomy or root avulsion. Few or no p75 positive motoneurons were observed after distal axotomy in animals at the age of postnatal day 1 and postnatal day 7, whereas the injury induced marked neuronal death. Motoneurons reexpressed p75 from the end of the second postnatal week to adulthood in response to distal axotomy, whereas most motoneurons survived after the injury. On the other hand, root avulsion in animals of all ages did not cause significant p75 expression in avulsed motoneurons where most motoneurons died ultimately. The potential role of such reexpression in motoneuron protection is discussed.

Age Factors↗

PubMed2006

Nano neuro knitting: peptide nanofiber scaffold for brain repair and axon regeneration with functional return of vision.

Nanotechnology is often associated with materials fabrication, microelectronics, and microfluidics. Until now, the use of nanotechnology and molecular self assembly in biomedicine to repair injured brain structures has not been explored. To achieve axonal regeneration after injury in the CNS, several formidable barriers must be overcome, such as scar tissue formation after tissue injury, gaps in nervous tissue formed during phagocytosis of dying cells after injury, and the failure of many adult neurons to initiate axonal extension. Using the mammalian visual system as a model, we report that a designed self-assembling peptide nanofiber scaffold creates a permissive environment for axons not only to regenerate through the site of an acute injury but also to knit the brain tissue together. In experiments using a severed optic tract in the hamster, we show that regenerated axons reconnect to target tissues with sufficient density to promote functional return of vision, as evidenced by visually elicited orienting behavior. The peptide nanofiber scaffold not only represents a previously undiscovered nanobiomedical technology for tissue repair and restoration but also raises the possibility of effective treatment of CNS and other tissue or organ trauma.

Aging↗

PubMed2006

Developmental changes of nitric oxide synthase expression in the rat hypothalamoneurohypophyseal system.

The present study investigated the immunohistochemical localization of neuronal nitric oxide synthase (nNOS) in the hypothalamoneurohypophyseal system (HNS) of the developing rats on postnatal day 1 (PN1), 7 (PN7), 14 (PN14), 21 (PN21), and the adult rats. The nNOS-positive neurons were not discernable in the supraoptic nucleus (SON), the paraventricular nucleus (PVN), and the median eminence (ME) at PN1 and PN7. A few neurons positive for nNOS were first detected at PN14. At PN21, the nNOS-positive cells in SON and PVN rapidly increased in number. The pattern of nNOS expression at this stage approached that of the adult. Moreover, the increase of nNOS expression in the SON and PVN during the postnatal period was accompanied by the maturation of arginine vasopressin (AVP) and oxytocin (OT) neurons as indicated by the number and size of OT or AVP neurons in the SON and PVN. The patterns of AVP versus OT expression also reached that of the adult by the end of the third postnatal week. The time course of the change in nNOS expression coincided with the maturation of AVP and OT neurons in the HNS and suggested that NO synthesized by conversion of NOS is involved in the modulation of activity of neurons in the SON and PVN of the HNS.

Animals↗

PubMed2006

Beta-amyloid peptides induces neuronal apoptosis via a mechanism independent of unfolded protein responses.

Accumulation of beta-amyloid (Abeta) peptides in senile plaques is one of the pathological hallmarks in Alzheimer's disease (AD), which can trigger apoptosis. We have previously demonstrated that Abeta triggered calcium release from the ER. Depletion of ER Ca(2+) ions has been reported leading to unfolded protein responses (UPR). While hypothesis has been made about UPR and neurodegeneration in AD, little is known about the effects of extracellular accumulation of Abeta on UPR. We have shown previously that activation of PKR in Abeta-triggered apoptosis. Since UPR can trigger PKR, our study aims to elucidate whether extracellular accumulation of Abeta peptides induce UPR in cultured neurons. Our results showed that Abeta could not trigger UPR signalings including phosphorylation of PERK, alternative cleavage of xbp-1 mRNA and induction of transcription of xbp-1 and Gadd153. Taken together, our results suggest that extracellular accumulation of Abeta peptides induce apoptosis via a mechanism independent of UPR.

Amyloid beta-Peptides↗

PubMed2006

Changes of retinal functions following the induction of ocular hypertension in rats using argon laser photocoagulation.

BACKGROUND: Electroretinography (ERG) provides a longitudinal monitoring of pathological changes in retina. Scotopic threshold response (STR) of ERG was shown to reflect inner retinal activity and is particularly useful in the evaluation of inner retinal changes in ocular hypertension models. Recently, STR was demonstrated to be attenuated after the induction of ocular hypertension using injection of hypertonic saline into episcleral veins which indicates an impairment of retinal function. However, little is known on the changes of retinal function in an ocular hypertension model induced by laser photocoagulation at episcleral veins and limbal veins. METHODS: Ocular hypertension was induced unilaterally using laser photocoagulation at episcleral veins and limbal veins in adult Sprague-Dawley rats. Intraocular pressure was monitored and the number of retinal ganglion cell loss was counted across the 8-week experimental period. The animals were dark adapted overnight and flash ERGs were measured before the laser treatment, 5 and 8 weeks after treatment. The changes of STR, scotopic negative response, a-wave and b-wave were analysed. RESULTS: Approximately 1.6-fold elevation of intraocular pressure was induced in the experimental eyes and 3% retinal ganglion cell loss per week was found. The amplitude of STR was significantly attenuated which indicates an impairment of inner retinal activities. There was also a reduction of scotopic negative response, a-wave and b-wave after the induction of ocular hypertension. CONCLUSION: The laser-induced ocular hypertension model in the present study produced a substantial reduction of retinal functions. Understanding the characteristic of pathological changes is crucial for further study using this model.

Animals↗

PubMed2006

Melanopsin-expressing retinal ganglion cells are more injury-resistant in a chronic ocular hypertension model.

PURPOSE: To investigate the survival of melanopsin-expressing retinal ganglion cells (mRGCs) after the induction of chronic ocular hypertension. METHODS: Intraocular pressure (IOP) was elevated in adult Sprague-Dawley rats using an argon laser to photocoagulate the episcleral and limbal veins. IOP was measured with a calibrated tonometer and monitored for a period. Seven days before the animals were killed, a piece of sterile foam soaked with gold fluorescent dye was placed onto the superior colliculus (SC) to label the SC-projecting retinal ganglion cells (scRGCs) retrogradely. mRGCs were visualized by free floating immunohistochemistry on whole-mounted retinas. The number of surviving scRGCs and mRGCs were counted on flatmounted retinas. The branching pattern of dendrites and soma size of mRGCs were examined. RESULTS: An approximately 1.7-fold increase of IOP and a significant loss of scRGCs were found in experimental eyes after laser photocoagulation. However, no significant cell loss or morphologic changes on mRGCs and their dendrites after the induction of chronic ocular hypertension are noticed over a 12-week period. CONCLUSIONS: Although the degeneration of retinal ganglion cells (RGCs) is a major concern in glaucomatous damage, the findings show that mRGCs are less susceptible to death after the induction of chronic ocular hypertension. This result indicates that mRGCs carry some unique properties that are different from those of other subpopulations of RGCs. The immunohistochemistry approach can be used to distinguish easily these mRGCs from other subtypes. This method provides a useful tool to investigate their injury-resistant properties that are informative for the development of effective neuroprotective treatment for glaucoma.

Animals↗

PubMed2006

Cytoprotective effects of Lycium barbarum against reducing stress on endoplasmic reticulum.

Chinese medicinal herbs have been consumed for thousands of years for the purpose of healthy aging. Lycium barbarum is valued in Chinese culture for its benefits to anti-aging, vision, kidney and liver. Recent studies showed that extracts from L. barbarum possess biological activities including anti-aging, anti-tumor, immune-stimulatory and cytoprotection. Most of these studies emphasized that the protective function of L. barbarum is due to its anti-oxidative effects. We have previously demonstrated that extract from L. barbarum can protect neurons against beta-amyloid (Abeta) peptide-induced apoptosis. Since Abeta toxicity may be mediated via oxidative stress, it is still unclear whether the extract from L. barbarum is a simple anti-oxidant exhibiting cytoprotective effects. We hypothesized that extract from L. barbarum is not simply an anti-oxidant in order to function as a neuroprotective agent. The aim of this study is to investigate whether the extract from L. barbarum (LBG) protect neurons via mechanisms independent of anti-oxidative effects. Using a reducing agent, dithiothreitol (DTT), we found that LBG exhibits cytoprotective effects against reducing stress by lowering the DTT-induced LDH release and caspase-3 activity. DTT can trigger endoplasmic reticulum (ER) stress leading to PKR-like ER kinase (PERK) activation. We also showed that LBG attenuates DTT-induced PERK phosphorylation. The extract from L. barbarum is not simply an anti-oxidant; it can also exhibit cytoprotective effects against reducing stress by DTT.

Animals↗

PubMed2005

Light delays synaptic deafferentation and potentiates the survival of axotomized retinal ganglion cells.

Knowledge of the cellular mechanism underlying the therapeutic effect of stimulation and the optimal doses of such stimulation to maximize neuronal recovery is essential to guide clinical practice in neural rehabilitation. Using hamsters, we transected the optic nerve to demonstrate how light stimulation affects neuronal recovery. The c-fos protein was used as a neuronal connectivity marker. Here we show that: (a) in addition to cell death, a population of cells undergoes synaptic deafferentation and (b) light stimulation delays cell death and deafferentation. Among the three rearing conditions studied (6:18LD, 12:12LD, and 18:6LD), the 12:12LD condition appears to be the one achieving the optimal therapeutic effect. This study provides a solid base in the understanding of the neuroanatomical changes after traumatic brain injury and the need to establish an optimal level and timing for the environmental stimulation.

Animals↗

PubMed2005

Different optic nerve injury sites result in different responses of retinal ganglion cells to brain-derived neurotrophic factor but not neurotrophin-4/5.

In this study, we investigated whether brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) can achieve prolonged protection on retinal ganglion cells (RGCs) and whether site of axon injury modulates RGC response to neurotrophins. Two optic nerve (ON) injury paradigms, proximal and distal transections, were used. Autologous sciatic nerves were grafted onto ON stump in some animals to provide a suitable environment for axons to regrow. Multiple intravitreal injections of saline, BDNF, or NT-4/5 were performed. Immunohistochemistry was used to determine the proportion of RGCs that were expressing trkB. Twenty days after proximal injury, both BDNF and NT-4/5 promoted RGC survival; this protection diminished 30 days after injury. One month after distal injury, BDNF, but not NT-4/5, promoted RGC survival (by 2-fold). No difference in the proportion of trkB expressing RGCs among the viable ones was seen between the two injury models or after BDNF treatment. Interestingly, the mean size of RGC somata was larger after proximal injury than distal injury. This study demonstrates that (1) RGCs respond differently to neurotrophins under different injury conditions, (2) BDNF but not NT-4/5 significantly enhances survival of distally but not proximally injured RGCs over a prolonged period.

Animals↗

PubMed2005

Electroacupuncture provides a new approach to neuroprotection in rats with induced glaucoma.

OBJECTIVES: To investigate, using multifocal electroretinogram (mfERG), the effect of electroacupuncture (EA) on retinal function in rats with experimental glaucoma. DESIGN AND SUBJECTS: Glaucoma was induced in the right eyes of 15 adult female Sprague-Dawley rats by laser photocoagulation for three quarters of the perilimbal and episcleral vessels. The left eye of each rat was used as the control. The animals were divided into 3 groups: no treatment (non-EA control group), 2 Hz EA group, and 100 Hz EA group. EA treatment at different frequencies can produce different levels of analgesia and hence the effect of EA with different frequencies on glaucoma treatment was investigated. Both eyes of each rat in the EA experimental groups received 3 EA treatment sessions each week for 4 weeks. The retinal function was measured using mfERG after 4 weeks of EA treatment. RESULTS: There was no significant difference in the amplitude (both N1 trough and P1 peak) of mfERG firstorder kernel response between the treatment and control groups. In determining the waveform characteristics by the ratio of N1 amplitude to P1 amplitude (N/P ratio), obvious differences were found in the N/P ratio between the control eyes and the glaucoma eyes in the non-EA group and the 100 Hz EA treatment group, but similar values in the N/P ratio were observed between the control eyes and the glaucoma eyes in the 2 Hz EA treatment group. The waveform from the eyes with glaucoma was deformed in both the non-EA group and the 100 Hz EA group, but the waveform from the glaucomatous eye was preserved in the 2 Hz EA group. CONCLUSIONS: Application of EA at 2 Hz provides neuroprotection by preserving retinal function in rats with experimental glaucoma. Low frequency EA may be an alternative therapy in the treatment of glaucoma.

Animals↗

PubMed2005

CNTF and BDNF have similar effects on retinal ganglion cell survival but differential effects on nitric oxide synthase expression soon after optic nerve injury.

PURPOSE: To investigate the effect of ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) on retinal ganglion cell (RGC) survival and nitric oxide synthase (NOS) expression in the retina during the early phase of optic nerve (ON) injury, and to examine whether intraperitoneal application of the NOS scavenger nitro-l-arginine (l-NA) could protect the injured RGCs. METHODS: RGCs were retrogradely labeled with granular blue 3 days before the ON was intraorbitally transected. RGC survival was examined 1 week after ON transection and intraocular injection of CNTF and/or BDNF, or 1 to 2 weeks after daily intraperitoneal injection of the NOS inhibitor l-NA. NOS expression was examined by NADPH-diaphorase histochemistry and neuronal NOS (nNOS) immunohistochemistry, and nNOS-positive cells were identified by various staining approaches. RESULTS: Both CNTF and BDNF significantly increased RGC survival 1 week after ON injury. In the ganglion cell layer (GCL), CNTF did not increase the number of NADPH-diaphorase positive ((+)) cells but appeared to reduce the intensity of NADPH-diaphorase staining, whereas BDNF increased the number of NADPH-diaphorase(+) cells and also appeared to enhance the intensity of NADPH-diaphorase staining. In the GCL, amacrine cells but not RGCs were nNOS(+). Some macrophages were also nNOS(+). In contrast, no amacrine cells were nNOS(+) in the inner nuclear layer. Daily intraperitoneal injection of l-NA at appropriate concentrations promoted RGC survival for 1 or 2 weeks after ON injury. CONCLUSIONS: Both CNTF and BDNF protected RGCs after ON injury. CNTF and BDNF acted differently on NOS expression in the GCL. Intraperitoneal injections of l-NA at appropriate dosages enhance RGC survival.

Animals↗

PubMed2005

Transgenic mice expressing Cre-recombinase specifically in retinal rod bipolar neurons.

PURPOSE: To establish a transgenic mouse line that expresses Cre-recombinase in retinal rod bipolar cells for the generation of rod bipolar cell-specific knockout mutants. METHODS: The IRES-Cre-cDNA fragment was inserted into a 173-kb bacterial artificial chromosome (BAC) carrying the intact Pcp2 gene, by using red-mediated recombineering. Transgenic mice were generated with the modified BAC and identified. The Cre-transgenic mice were crossed with ROSA26 and Z/EG reporter mice to detect Cre-recombinase activity. RESULTS: X-gal staining showed that strong Cre-recombinase activities were present in retinal inner nuclear layers and cerebellar Purkinje cells. Double staining with an anti-GFP antibody and an anti-PKCalpha antibody (specific for retinal rod bipolar cells) revealed that Cre-recombinase activity localized exclusively to the rod bipolar cells in the retina. CONCLUSIONS: A mouse BAC-Pcp2-IRES-Cre transgenic line that expresses Cre-recombinase in retinal rod bipolar neurons has been established. Because mutations in some ubiquitously expressed genes may result in retinal degenerative diseases, the mouse strain BAC-Pcp2-IRES-Cre will be a useful new tool for investigating the effects of retinal rod bipolar cell-specific gene inactivation.

Animals↗