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1.  Effects of low level laser treatment on the survival of axotomized retinal ganglion cells in adult Hamsters 
Neural Regeneration Research  2014;9(21):1863-1869.
Injury to axons close to the neuronal bodies in the mammalian central nervous system causes a large proportion of parenting neurons to degenerate. It is known that optic nerve transection close to the eye in rodents leads to a loss of about half of retinal ganglion cells in 1 week and about 90% in 2 weeks. Using low level laser treatment in the present study, we demonstrated that treatment with helium-neon (660 nm) laser with 15 mW power could delay retinal ganglion cell death after optic nerve axotomy in adult hamsters. The effect was most apparent in the first week with a short period of treatment time (5 minutes) in which 65–66% of retinal ganglion cells survived the optic nerve axotomy whereas 45–47% of retinal ganglion cells did so in optic nerve axotomy controls. We also found that single dose and early commencement of laser irradiation were important in protecting retinal ganglion cells following optic nerve axotomy. These findings thus convincingly show that appropriate laser treatment may be neuroprotective to retinal ganglion cells.
doi:10.4103/1673-5374.145337
PMCID: PMC4281419  PMID: 25558230
low level laser treatment; retinal ganglion cells; optic nerve injury; neuroprotection; microglial proliferation; optic nerve axotomy
2.  Choosing preclinical study models of diabetic retinopathy: key problems for consideration 
Diabetic retinopathy (DR) is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. However, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study models of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR.
doi:10.2147/DDDT.S72797
PMCID: PMC4242133  PMID: 25429204
animal model; in vitro culture; ex vivo culture; neurovascular dysfunction
3.  The current research status of normal tension glaucoma 
Normal tension glaucoma (NTG) is a progressive optic neuropathy that mimics primary open-angle glaucoma, but lacks the findings of elevated intraocular pressure or other mitigating factors that can lead to optic neuropathy. The present review summarized the causes, genetics, and mechanisms underlying NTG in both animal models and human patients. We also proposed that the neurovascular unit is a therapeutic target for NTG management.
doi:10.2147/CIA.S67263
PMCID: PMC4172068  PMID: 25258525
aging; genetics; neurovascular unit; primary open-angle glaucoma; treatment
4.  Physical Exercise-Induced Adult Neurogenesis: A Good Strategy to Prevent Cognitive Decline in Neurodegenerative Diseases? 
BioMed Research International  2014;2014:403120.
Cumulative evidence has indicated that there is an important role for adult hippocampal neurogenesis in cognitive function. With the increasing prevalence of cognitive decline associated with neurodegenerative diseases among the ageing population, physical exercise, a potent enhancer of adult hippocampal neurogenesis, has emerged as a potential preventative strategy/treatment to reduce cognitive decline. Here we review the functional role of adult hippocampal neurogenesis in learning and memory, and how this form of structural plasticity is altered in neurodegenerative diseases known to involve cognitive impairment. We further discuss how physical exercise may contribute to cognitive improvement in the ageing brain by preserving adult neurogenesis, and review the recent approaches for measuring changes in neurogenesis in the live human brain.
doi:10.1155/2014/403120
PMCID: PMC4000963  PMID: 24818140
5.  Mechanisms of secondary degeneration after partial optic nerve transection 
Neural Regeneration Research  2014;9(6):565-574.
Secondary degeneration occurs commonly in the central nervous system after traumatic injuries and following acute and chronic diseases, including glaucoma. A constellation of mechanisms have been shown to be associated with secondary degeneration including apoptosis, necrosis, autophagy, oxidative stress, excitotoxicity, derangements in ionic homeostasis and calcium influx. Glial cells, such as microglia, astrocytes and oligodendrocytes, have also been demonstrated to take part in the process of secondary injury. Partial optic nerve transection is a useful model which was established about 13 years ago. The merit of this model compared with other optic nerve injury models used for glaucoma study, including complete optic nerve transection model and optic nerve crush model, is the possibility to separate primary degeneration from secondary degeneration in location. Therefore, it provides a good tool for the study of secondary degeneration. This review will focus on the research progress of the mechanisms of secondary degeneration using partial optic nerve transection model.
doi:10.4103/1673-5374.130093
PMCID: PMC4146235  PMID: 25206855
secondary degeneration; partial injury; optic nerve; oxidative stress; excitotoxicity; calcium overload; mitochondrion; macrophage; astrocyte; oligodendrocyte
6.  Occurrence of new neurons in the piriform cortex 
Adult neurogenesis has been well studied in hippocampus and subventricular zone (SVZ); while this is much less appreciated in other brain regions, including amygdala, hypothalamus, and piriform cortex (PC). The present review aims at summarizing recent advances on the occurrence of new neurons in the PC, their potential origin, and migration route from the SVZ. We further discuss the relevant implications in olfactory dysfunction accompanying the neurodegenerative diseases.
doi:10.3389/fnana.2014.00167
PMCID: PMC4301012  PMID: 25653597
adult neurogenesis; piriform cortex; epilepsy; degeneration; Alzheimer’s disease; Parkinson’s disease; olfaction
7.  Acupuncture improves cognitive function: A systematic review☆ 
Neural Regeneration Research  2013;8(18):1673-1684.
BACKGROUND:
Acupuncture has been used as a treatment for cognitive impairment.
OBJECTIVE:
This review assesses clinical evidence for or against acupuncture as a treatment for cognitive impairment. This review also discusses the proposed mechanism(s) that could link acupuncture to improved cognitive function.
METHODS:
We searched the literature using PolyUone search from its inception to January 2013, with full text available and language limited to English. Levels of evidence were examined using Oxford Centre for Evidence-based Medicine–Levels of Evidence (March, 2009).
RESULTS:
Twelve studies met the inclusion criteria: 3 human studies and 9 animal studies. Levels of evidence ranged from level 1b to level 5.
CONCLUSION:
Most animal studies demonstrated a positive effect of acupuncture on cognitive impairment. However, the results of human studies were inconsistent. Further high-quality human studies with greater statistical power are needed to determine the effectiveness of acupuncture and an optimal protocol.
doi:10.3969/j.issn.1673-5374.2013.18.005
PMCID: PMC4145916  PMID: 25206464
neural regeneration; dementia; acupuncture; electroacupuncture; learning; cognitive; cognition; memory; neuroregeneration
8.  Pre-ischemia electro-acupuncture potentiates the expression of Bcl-2 and transforming growth factor-beta 1 in rat brains☆ 
Neural Regeneration Research  2012;7(24):1859-1865.
The expression of the anti-apoptotic molecules Bcl-2 and transforming growth factor-beta 1 is known to confer protective effects on the cerebral ischemia-reperfusion injury. The current study investigated the expression levels of Bcl-2 and transforming growth factor-beta 1 in response to multiple pre-ischemia electro-acupuncture at acupoints Zusanli (ST36) and Fengchi (GB20) stimulation. Rats were divided into five groups: uninjured, control, non-acupoint, GB20 and ST36. Rats in the non-acupoint, GB20 and ST36 groups received 30 minutes (3 times or 18 times) of electro-acupuncture stimulation before experimental cerebral ischemia was induced. Bcl-2 and transforming growth factor-beta 1 were found to be significantly increased in the ST36 groups with either 3 or 18 electro-acupuncture treatments (P < 0.05). The production was higher with 18 electro-acupuncture treatments in the ST36 groups (P < 0.05). In the GB20 groups, significant increase was only observed in transforming growth factor-beta 1 with 18 electro-acupuncture treatments (P < 0.05). No significant elevation of the level of transforming growth factor-beta 1 was observed in the non-acupoint groups. However, the production of Bcl-2 increased with 18 treatments in the non-acupoint groups (P < 0.05). The data suggest that multiple pre-ischemia electro-acupuncture at ST36 was effective in conferring neuroprotective effect on the brain by means of upregulation of Bcl-2 and transforming growth factor-beta 1 and the effect was increase with the number of treatment.
doi:10.3969/j.issn.1673-5374.2012.24.003
PMCID: PMC4298899  PMID: 25624811
cerebral ischemia; stroke prevention; electro-acupuncture; transforming growth factor-beta 1; Bcl-2; acupoint
9.  Retinal structure and function preservation by polysaccharides of wolfberry in a mouse model of retinal degeneration 
Scientific Reports  2014;4:7601.
Retinitis pigmentosa (RP) is a heterogeneous group of inherited disorders caused by mutations in a variety of genes that are mostly expressed by rod cells, which results in initial death of rod photoreceptors followed by gradual death of cone photoreceptors. RP is currently untreatable and usually leads to partial or complete blindness. Here, we explored the potential neuroprotective effects of polysaccharides of wolfberry, which are long known to possess primary beneficial properties in the eyes, on photoreceptor apoptosis in the rd10 mouse model of RP. We found that these polysaccharides provided long-term morphological and functional preservation of photoreceptors and improved visual behaviors in rd10 mice. Moreover, we demonstrated that polysaccharides exerted neuroprotective effects through antioxidant, anti-inflammatory and anti-apoptotic mechanisms. Furthermore, we identified that polysaccharides modulated inflammation and apoptosis partly through inhibition of NF-κB and HIF-1α expressions, respectively. Overall, we demonstrated the synergistic protective effects of polysaccharides in preserving photoreceptors against degeneration in rd10 mice. Our study provides rationale and scientific support on using polysaccharides of wolfberry as one supplementary treatment of RP patients in the future.
doi:10.1038/srep07601
PMCID: PMC4274520  PMID: 25535040
10.  Dendritic Morphology of Caudal Periaqueductal Gray Projecting Retinal Ganglion Cells in Mongolian Gerbil (Meriones unguiculatus) 
PLoS ONE  2014;9(7):e103306.
In this study we investigated the morphological features of the caudal periaqueductal gray (cPAG)-projecting retinal ganglion cells (RGCs) in Mongolian gerbils using retrograde labeling, in vitro intracellular injection, confocal microscopy and three-dimensional reconstruction approaches. cPAG-projecting RGCs exhibit small somata (10–17 µm) and irregular dendritic fields (201–298 µm). Sizes of somata and dendritic fields do not show obvious variation at different distance from the optic disk (eccentricity). Dendrites are moderately branched. Morphological analysis (n = 23) reveals that cPAG-projecting RGCs ramified in sublamina a and b in the inner plexiform layer. These cells exhibit different stratification patterns based on the thickness of dendritic bands in sublaminas a and b: majority of analyzed cells (16 out of 23) have two bands of arborizations share similar thickness. The rest of analyzed cells (7 out of 23) exhibit thinner band in sublamina a than in sublamina b. Together, the present study suggests that cPAG of Mongolian gerbil could receive direct retinal inputs from two types of bistratified RGCs. Furthermore, a small subset of melanopsin-expressing RGCs (total 41 in 6 animals) is shown to innervate the rostral PAG (rPAG). Functional characteristics of these non-visual center projecting RGCs remain to be determined.
doi:10.1371/journal.pone.0103306
PMCID: PMC4108400  PMID: 25054882
11.  Functional Motor Recovery from Motoneuron Axotomy Is Compromised in Mice with Defective Corticospinal Projections 
PLoS ONE  2014;9(7):e101918.
Brachial plexus injury (BPI) and experimental spinal root avulsion result in loss of motor function in the affected segments. After root avulsion, significant motoneuron function is restored by re-implantation of the avulsed root. How much this functional recovery depends on corticospinal inputs is not known. Here, we studied that question using Celsr3|Emx1 mice, in which the corticospinal tract (CST) is genetically absent. In adult mice, we tore off right C5–C7 motor and sensory roots and re-implanted the right C6 roots. Behavioral studies showed impaired recovery of elbow flexion in Celsr3|Emx1 mice compared to controls. Five months after surgery, a reduced number of small axons, and higher G-ratio of inner to outer diameter of myelin sheaths were observed in mutant versus control mice. At early stages post-surgery, mutant mice displayed lower expression of GAP-43 in spinal cord and of myelin basic protein (MBP) in peripheral nerves than control animals. After five months, mutant animals had atrophy of the right biceps brachii, with less newly formed neuromuscular junctions (NMJs) and reduced peak-to-peak amplitudes in electromyogram (EMG), than controls. However, quite unexpectedly, a higher motoneuron survival rate was found in mutant than in control mice. Thus, following root avulsion/re-implantation, the absence of the CST is probably an important reason to hamper axonal regeneration and remyelination, as well as target re-innervation and formation of new NMJ, resulting in lower functional recovery, while fostering motoneuron survival. These results indicate that manipulation of corticospinal transmission may help improve functional recovery following BPI.
doi:10.1371/journal.pone.0101918
PMCID: PMC4087004  PMID: 25003601
12.  Lycium barbarum polysaccharides therapeutically improve hepatic functions in non-alcoholic steatohepatitis rats and cellular steatosis model 
Scientific Reports  2014;4:5587.
This study aimed to investigate the possible therapeutic effects and active components of Lycium barbarum polysaccharides (LBP) on a high fat diet-induced NASH rat model. We induced NASH in a rat model by voluntary oral feeding with a high-fat diet ad libitum for 8 weeks. After 8 weeks, 1 mg/kg LBP was orally administered for another 4 weeks with a high-fat diet. When compared with NASH rats treated for 12 weeks, therapeutic LBP treatment for 4 weeks during 12 weeks of NASH induction showed ameliorative effects on: (1) increased body and wet liver weights; (2) insulin resistance and glucose metabolic dysfunction; (3) elevated level of serum aminotransferases; (4) fat accumulation in the liver and increased serum free fatty acid (FFA) level; (5) hepatic fibrosis; (6) hepatic oxidative stress; (7) hepatic inflammatory response; and (8) hepatic apoptosis. These improvements were partially through the modulation of transcription factor NF-κB, MAPK pathways and the autophagic process. In a palmitate acid-induced rat hepatocyte steatosis cell–based model, we also demonstrated that l-arabinose and β-carotene partially accounted for the beneficial effects of LBP on the hepatocytes. In conclusion, LBP possesses a variety of hepato-protective properties which make it a potent supplementary therapeutic agent against NASH in future clinical trials.
doi:10.1038/srep05587
PMCID: PMC4083265  PMID: 24998389
13.  Lithium Enhances Axonal Regeneration in Peripheral Nerve by Inhibiting Glycogen Synthase Kinase 3β Activation 
BioMed Research International  2014;2014:658753.
Brachial plexus injury often involves traumatic root avulsion resulting in permanent paralysis of the innervated muscles. The lack of sufficient regeneration from spinal motoneurons to the peripheral nerve (PN) is considered to be one of the major causes of the unsatisfactory outcome of various surgical interventions for repair of the devastating injury. The present study was undertaken to investigate potential inhibitory signals which influence axonal regeneration after root avulsion injury. The results of the study showed that root avulsion triggered GSK-3β activation in the injured motoneurons and remaining axons in the ventral funiculus. Systemic application of a clinical dose of lithium suppressed activated GSK-3β in the lesioned spinal cord to the normal level and induced extensive axonal regeneration into replanted ventral roots. Our study suggests that GSK-3β activity is involved in negative regulation for axonal elongation and regeneration and lithium, the specific GSK-3β inhibitor, enhances motoneuron regeneration from CNS to PNS.
doi:10.1155/2014/658753
PMCID: PMC4055222  PMID: 24967390
14.  Zeaxanthin Dipalmitate Therapeutically Improves Hepatic Functions in an Alcoholic Fatty Liver Disease Model through Modulating MAPK Pathway 
PLoS ONE  2014;9(4):e95214.
In the current study, the therapeutic effects of zeaxanthin dipalmitate (ZD) on a rat alcoholic fatty liver disease (AFLD) model were evaluated. After-treatment with ZD from the 5th week to the 10th week in a 10-week ethanol intragastric administration in rats significantly alleviated the typical AFLD symptoms, including reduction in rat body weight, accumulation of hepatic fat droplets, occurrence of oxidative stress, inflammation, chemoattractive responses and hepatic apoptosis in the liver. The reduction of liver function abnormalities by ZD was partly through lower expression level of cytochrome P450 2E1 (CYP2E1), diminished activity of nuclear factor kappa B (NF-κB) through the restoration of its inhibitor kappa B alpha (IκBα), and the modulation of MAPK pathways including p38 MAPK, JNK and ERK. ZD treatment alone did not pose obvious adverse effect on the healthy rat. In the cellular AFLD model, we also confirmed the inhibition of p38 MAPK and ERK abolished the beneficial effects of ZD. These results provide a scientific rationale for the use of zeaxanthin and its derivatives as new complementary agents for the prevention and treatment of alcoholic liver diseases.
doi:10.1371/journal.pone.0095214
PMCID: PMC3989301  PMID: 24740309
15.  Chinese Traditional Medicine and Adult Neurogenesis in the Hippocampus 
Adult neurogenesis is an important therapeutic target in treating neurological disorders. Adult neurogenesis takes place in two regions of the brain: Subventricular zone and dentate gyrus in the hippocampus. The progressive understanding on hippocampal neurogenesis in aging and mood disorders increases the demand to explore powerful and subtle interventions on hippocampal neurogenesis. Traditional Chinese herbal medicine provides an abundant pharmaceutical platform for modulating hippocampal neurogenesis. Recent progress in exploring the effects of Chinese herbal medicine and the related mechanisms opens a new direction for regeneration therapy. The current review gives a thorough summary of the research progress made in traditional Chinese herbal formulas, and the effective compounds in Chinese herbs which are beneficial on hippocampal neurogenesis and the possible mechanisms involved.
doi:10.4103/2225-4110.130372
PMCID: PMC4003705  PMID: 24860729
Active components; Hippocampal neurogenesis; Neural progenitor cells; Traditional Chinese herb
16.  Dipping cells in acidic bath could make stem cells 
Neural Regeneration Research  2014;9(6):575-576.
doi:10.4103/1673-5374.130087
PMCID: PMC4146237  PMID: 25206856
17.  Activation of the Nrf2/HO-1 Antioxidant Pathway Contributes to the Protective Effects of Lycium Barbarum Polysaccharides in the Rodent Retina after Ischemia-Reperfusion-Induced Damage 
PLoS ONE  2014;9(1):e84800.
Lycium barbarum polysaccharides (LBP), extracts from the wolfberries, are protective to retina after ischemia-reperfusion (I/R). The antioxidant response element (ARE)–mediated antioxidant pathway plays an important role in maintaining the redox status of the retina. Heme oxygenase-1 (HO-1), combined with potent AREs in its promoter, is a highly effective therapeutic target for the protection against neurodegenerative diseases, including I/R-induced retinal damage. The aim of our present study was to investigate whether the protective effect of LBP after I/R damage was mediated via activation of the Nrf2/HO-1-antioxidant pathway in the retina. Retinal I/R was induced by an increase in intraocular pressure to 130 mm Hg for 60 minutes. Prior to the induction of ischemia, rats were orally treated with either vehicle (PBS) or LBP (1 mg/kg) once a day for 1 week. For specific experiments, zinc protoporphyrin (ZnPP, 20 mg/kg), an HO-1 inhibitor, was intraperitoneally administered at 24 h prior to ischemia. The protective effects of LBP were evaluated by quantifying ganglion cell and amacrine cell survival, and by measuring cell apoptosis in the retinal layers. In addition, HO-1 expression was examined using Western blotting and immunofluorescence analyses. Cytosolic and nuclear Nrf2 was measured using immunofluorescent staining. LBP treatment significantly increased Nrf2 nuclear accumulation and HO-1 expression in the retina after I/R injury. Increased apoptosis and a decrease in the number of viable cells were observed in the ganglion cell layer (GCL) and inner nuclear layer (INL) in the I/R retina, which were reversed by LBP treatment. The HO-1 inhibitor, ZnPP, diminished the LBP treatment-induced protective effects in the retina after I/R. Taken together, these results suggested that LBP partially exerted its beneficial neuroprotective effects via the activation of Nrf2 and an increase in HO-1 protein expression.
doi:10.1371/journal.pone.0084800
PMCID: PMC3882254  PMID: 24400114
18.  Letter from Editors-in-Chief 
doi:10.4103/1673-5374.125320
PMCID: PMC4146322  PMID: 25206735
19.  Effect of Lycium Barbarum (Wolfberry) Polysaccharides on Preserving Retinal Function after Partial Optic Nerve Transection 
PLoS ONE  2013;8(12):e81339.
Lycium Barbarum Polysaccharides (LBP) are the active components of Wolfberry (a traditional Chinese medicine) which has long been used for improving visual function. This study aims to investigate localized changes of retinal function in a partial optic nerve transection (PONT) model, and effects of LBP on visual function. The multifocal electroretinograms (mfERG) were obtained from 30 eyes of 30 Sprague-Dawley rats. The rats were divided into 6 groups (five treatment groups and one control group). Starting from the first day of the experiment, the rats in the (PONT+LBP) group and the (LBP) group were dosed with LBP; rats in the (PONT+PBS (phosphate buffered saline)) group and the (PBS) group were dosed with PBS via nasogastric tube every day until euthanized. The dorsal part of the optic nerve was transected in the (PONT), (PONT+LBP) and (PONT+PBS) groups at the end of week 1 (day 7 after LBP or PBS feeding began). The mfERG was measured at three time points: week 2, week 3 and week 5. Significant reduction of P1 and PhNR amplitudes of the mfERG were observed in all retinal regions a week after PONT. Feeding with LBP prior to PONT preserved retinal function. All mfERG responses returned to the normal range in the superior retina, which corresponds to the transected dorsal region of the optic nerve, while most of the inferior retinal responses were significantly increased at week 4 after PONT. The ventral part of the retina had secondary degeneration which was not only limited to the ganglion cell layer, but is a widespread effect affecting the outer retina. LBP altered the functional reduction caused by PONT by regulating the signal from the outer retina.
doi:10.1371/journal.pone.0081339
PMCID: PMC3858224  PMID: 24339917
20.  Oligomeric proanthocyanidin protects retinal ganglion cells against oxidative stress-induced apoptosis 
Neural Regeneration Research  2013;8(25):2317-2326.
The death of retinal ganglion cells is a hallmark of many optic neurodegenerative diseases such as glaucoma and retinopathy. Oxidative stress is one of the major reasons to cause the cell death. Oligomeric proanthocyanidin has many health beneficial effects including antioxidative and neuroprotective actions. Here we tested whether oligomeric proanthocyanidin may protect retinal ganglion cells against oxidative stress induced-apoptosis in vitro. Retinal ganglion cells were treated with hydrogen peroxide with or without oligomeric proanthocyanidin. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that treating retinal ganglion cell line RGC-5 cells with 20 μmol/L oligomeric proanthocyanidin significantly decreased the hydrogen peroxide (H2O2) induced death. Results of flow cytometry and Hoechst staining demonstrated that the death of RGC-5 cells was mainly caused by cell apoptosis. We further found that expression of pro-apoptotic Bax and caspase-3 were significantly decreased while anti-apoptotic Bcl-2 was greatly increased in H2O2 damaged RGC-5 cells with oligomeric proanthocyanidin by western blot assay. Furthermore, in retinal explant culture, the number of surviving retinal ganglion cells in H2O2-damaged retinal ganglion cells with oligomeric proanthocyanidin was significantly increased. Our studies thus demonstrate that oligomeric proanthocyanidin can protect oxidative stress-injured retinal ganglion cells by inhibiting apoptotic process.
doi:10.3969/j.issn.1673-5374.2013.25.002
PMCID: PMC4146041  PMID: 25206541
neural regeneration; traditional Chinese medicine; retinal ganglion cell; oligomeric proanthocyanidin; oxidative stress; hydrogen peroxide; retinal explants; apoptosis; grants-supported paper; neuroregeneration
21.  Lycium Barbarum (Wolfberry) Reduces Secondary Degeneration and Oxidative Stress, and Inhibits JNK Pathway in Retina after Partial Optic Nerve Transection 
PLoS ONE  2013;8(7):e68881.
Our group has shown that the polysaccharides extracted from Lycium barbarum (LBP) are neuroprotective for retinal ganglion cells (RGCs) in different animal models. Protecting RGCs from secondary degeneration is a promising direction for therapy in glaucoma management. The complete optic nerve transection (CONT) model can be used to study primary degeneration of RGCs, while the partial optic nerve transection (PONT) model can be used to study secondary degeneration of RGCs because primary degeneration of RGCs and secondary degeneration can be separated in location in the same retina in this model; in other situations, these types of degeneration can be difficult to distinguish. In order to examine which kind of degeneration LBP could delay, both CONT and PONT models were used in this study. Rats were fed with LBP or vehicle daily from 7 days before surgery until sacrifice at different time-points and the surviving numbers of RGCs were evaluated. The expression of several proteins related to inflammation, oxidative stress, and the c-jun N-terminal kinase (JNK) pathways were detected with Western-blot analysis. LBP did not delay primary degeneration of RGCs after either CONT or PONT, but it did delay secondary degeneration of RGCs after PONT. We found that LBP appeared to exert these protective effects by inhibiting oxidative stress and the JNK/c-jun pathway and by transiently increasing production of insulin-like growth factor-1 (IGF-1). This study suggests that LBP can delay secondary degeneration of RGCs and this effect may be linked to inhibition of oxidative stress and the JNK/c-jun pathway in the retina.
doi:10.1371/journal.pone.0068881
PMCID: PMC3716882  PMID: 23894366
22.  Ventral root re-implantation is better than peripheral nerve transplantation for motoneuron survival and regeneration after spinal root avulsion injury 
BMC Surgery  2013;13:21.
Background
Peripheral nerve (PN) transplantation and ventral root implantation are the two common types of recovery operations to restore the connection between motoneurons and their target muscles after brachial plexus injury. Despite experience accumulated over the past decade, fundamental knowledge is still lacking concerning the efficacy of the two microsurgical interventions.
Methods
Thirty-eight adult female Sprague–Dawley rats were divided into 5 groups. Immediately following root avulsion, animals in the first group (n = 8) and the second group (n = 8) received PN graft and ventral root implantation respectively. The third group (n = 8) and the fourth group (n = 8) received PN graft and ventral root implantation respectively at one week after root avulsion. The fifth group received root avulsion only as control (n = 6). The survival and axonal regeneration of severed motoneurons were investigated at 6 weeks post-implantation.
Results
Re-implantation of ventral roots, both immediately after root avulsion and in delay, significantly increased the survival and regeneration of motoneurons in the avulsed segment of the spinal cord as compared with PN graft transplantation.
Conclusions
The ventral root re-implantation is a better surgical repairing procedure than PN graft transplantation for brachial plexus injury because of its easier manipulation for re-implanting avulsed ventral roots to the preferred site, less possibility of causing additional damage and better effects on motoneuron survival and axonal regeneration.
doi:10.1186/1471-2482-13-21
PMCID: PMC3711737  PMID: 23799915
Avulsion; Peripheral nerve graft transplantation; Ventral root re-implantation; Motoneuron survival and regeneration
23.  Changes in Retinal Morphology, Electroretinogram and Visual Behavior after Transient Global Ischemia in Adult Rats 
PLoS ONE  2013;8(6):e65555.
The retina is a light-sensitive tissue of the central nervous system that is vulnerable to ischemia. The pathological mechanism underlying retinal ischemic injury is not fully understood. The purpose of this study was to investigate structural and functional changes of different types of rat retinal neurons and visual behavior following transient global ischemia. Retinal ischemia was induced using a 4-vessel occlusion model. Compared with the normal group, the number of βIII-tubulin positive retinal ganglion cells and calretinin positive amacrine cells were reduced from 6 h to 48 h following ischemia. The number of recoverin positive cone bipolar cells transiently decreased at 6 h and 12 h after ischemia. However, the fluorescence intensity of rhodopsin positive rod cells and fluorescent peanut agglutinin positive cone cells did not change after reperfusion. An electroretinogram recording showed that the a-wave, b-wave, oscillatory potentials and the photopic negative response were completely lost during ischemia. The amplitudes of the a- and b-waves were partially recovered at 1 h after ischemia, and returned to the control level at 48 h after reperfusion. However, the amplitudes of oscillatory potentials and the photopic negative response were still reduced at 48 h following reperfusion. Visual behavior detection showed there was no significant change in the time spent in the dark chamber between the control and 48 h group, but the distance moved, mean velocity in the black and white chambers and intercompartmental crosses were reduced at 48 h after ischemia. These results indicate that transient global ischemia induces dysfunction of retinal ganglion cells and amacrine cells at molecular and ERG levels. However, transient global ischemia in a 17 minute duration does not appear to affect photoreceptors.
doi:10.1371/journal.pone.0065555
PMCID: PMC3679137  PMID: 23776500
24.  Direct Retino-Raphe Projection Alters Serotonergic Tone and Affective Behavior 
Neuropsychopharmacology  2013;38(7):1163-1175.
Light is a powerful modulator of higher-order cognitive processes such as mood but it remains unclear which neural circuits mediate the impact of light on affective behavior. We found that light deprivation produces a depressive-like behavioral state that is reversed by activation of direct retinal signals to the serotonergic dorsal raphe nucleus (DRN) in a manner equivalent to treatment with the selective serotonin reuptake inhibitor fluoxetine. Surprisingly, the DRN-projecting retinal ganglion cells (RGCs) are indistinguishable from the classic alpha/Y-like RGC type that contributes to image-forming visual pathways. Silencing RGC firing or specific immunotoxin ablation of DRN-projecting RGCs increased depressive-like behavior and reduced serotonin levels in the DRN. Serotonin has a key role in the pathophysiology of depression, and these results demonstrate that retino-raphe signals modulate DRN serotonergic tone and affective behavior.
doi:10.1038/npp.2013.35
PMCID: PMC3656380  PMID: 23370156
Affective visual information; Animal models; Depression; Dorsal Raphe Nucleus; Fluoxetine; Mood; Anxiety; Stress Disorders; Neurophysiology; Retinal ganglion cells; Serotonin; dorsal raphe nucleus; retinal ganglion cell; depression; affective visual information; SSRI
25.  The effect of Lycium barbarum on spinal cord injury, particularly its relationship with M1 and M2 macrophage in rats 
Background
Our past researches suggested that L. barbarum exhibits direct neuroprotective and immune regulatory effects on the central nervous system, which are highly related to the events involved in the spinal cord injury, but not yet been investigated. Immune responses play an important role in the development of the pathology after secondary injury, particularly the M1 and M2 types of macrophage, on which special emphasis was laid in this study.
Methods
In our previous studies L. barbarum was administrated orally from 7 days before the injury to ensure a stabilized concentration in the blood. For clinical application, L. barbarum can only be administered after the injury. Therefore, both pre-injury and post-injury administration protocols were compared. In vivo and in vitro studies were conducted and analyzed immunohistochemically, including Western blotting.
Results
The lesion size in the pre-treated group was much larger than that in the post-treated group. To explain this difference, we first studied the effect of L. barbarum on astrocytes, which forms the glial scar encircling the lesion. L. barbarum did not significantly affect the astrocytes. Then we studied the effect of L. barbarum on microglia/macrophages, particularly the M1 and M2 polarization. After spinal cord injury, the deleterious M1 cells dominant the early period, whereas the beneficial M2 cells dominate later. We found that in the pre-treated group L. barbarum significantly enhanced the expression of M1 cells and suppressed that of M2 cells, while in the post-treated group LBP markedly promoted the activity of M2 cells. This explained the difference between the pre- and post-treated groups.
Conclusions
Lycium barbarum has been wildly accepted to have beneficial effects in various central nervous system diseases. Our finding of deleterious effect of LBP administered at early period of spinal cord injury, indicates that its application should be avoided. The substantial beneficial effect of LBP when administered at later stage has an important impact for clinical application.
doi:10.1186/1472-6882-13-67
PMCID: PMC3618261  PMID: 23517687
L. barbarum; Spinal cord injury; Macrophage; Rat

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