Nerve Growth Factor Treatment Research Articles

Efficacy and Safety of Nerve Growth Factor in Treating Neurotrophic Keratitis Patients: A Meta-Analysis.

Aims/Background Nerve growth factor has been approved for treating neurotrophic keratitis in Europe and the United States. However, its clinical efficacy and safety profile in neurotrophic keratitis patients have not been systematically evaluated. Therefore, this study systematically assessed the efficacy and safety of nerve growth factor (NGF) in treating patients with neurotrophic keratitis. Methods Various databases, including Wanfang, China National Knowledge Internet (CNKI), Embase, PubMed, and Web of Science were systematically searched. This search included all articles published up to January 2024. Moreover, these articles were thoroughly reviewed and carefully screened following predetermined inclusion and exclusion criteria. Furthermore, the quality of the included studies was assessed using the Cochrane Risk of Bias Manual 5.3 (The Cochrane Collaboration, London, UK). Stata26.0 (StataCorp LLC, College Station, TX, USA) was used for meta-analysis. The outcome indicators evaluated in this study included corneal healing efficiency, corneal complete healing rate, best vision correction rate, ailment progression, and the number of adverse events. Results A total of 4 articles were included in this study, including 293 sufferers. The findings from the meta-analysis revealed that the corneal healing efficiency (odds ratio (OR) = 1.72, 95% confidence interval (CI): 1.20-2.45), the corneal complete healing rate (OR = 2.23, 95% CI: 1.41-3.54), and the best visual acuity correction rate (OR = 1.97, 95% CI: 1.11-3.47) were significantly higher in the experimental group compared to the control group. However, the incidence of ailment progression (OR = 0.44, 95% CI: 0.17-1.13) and adverse events (OR = 0.88, 95% CI: 0.50-1.56) did not show significant differences between these two groups. Conclusion In summary, for patients with neuropathic keratitis, NGF treatment can promote corneal healing efficiency, effectively improve visual correction, and reduce disease progression and incidence of adverse events to a large extent. The clinical effect and safety are high, and it is worthy of clinical promotion and application.

Nerve growth factor alleviates arsenic-induced testicular injury by enhancing the function of Sertoli cells

Sertoli cells (SCs) maintain testicular homeostasis and promote spermatogenesis by forming the blood-testis barrier (BTB) and secreting growth factors. The pro-proliferative and anti-apoptotic effects of nerve growth factor (NGF) on SCs have been proved previously. It is still unclear whether the damage effect of arsenic on testis is related to the inhibition of NGF expression, and whether NGF can mitigate arsenic-induced testicular damage by decreasing the damage of SCs induced by arsenic. Here, the lower expression of NGF in testes of arsenic exposed mice (freely drinking water containing 15 mg/l of NaAsO2) was observed through detection of Western blot and Real-time PCR. Subsequently, hematoxylin and eosin (HE) staining, Evans blue staining and transmission electron microscopy were used to evaluate the pathology, BTB permeability and tight junction integrity in testes of control mice, arsenic exposed mice (freely drinking water containing 15 mg/l of NaAsO2) and arsenic + NGF treated mice (freely drinking water containing 15 mg/l of NaAsO2 + intraperitoneal injection with 30 μg/kg of NGF), respectively. Evidently, spermatogenic tubule epithelial cells in testis of arsenic exposed mice were disordered and the number of cell layers was reduced, accompanied by increased permeability and damaged integrity of the tight junction in BTB, but these changes were less obvious in testes of mice treated with arsenic + NGF. In addition, the sperm count, motility and malformation rate of mice treated with arsenic + NGF were also improved. On the basis of the above experiments, the viability and apoptosis of primary cultured SCs treated with arsenic (10 μM NaAsO2) or arsenic + NGF (10 μM NaAsO2 + 100 ng/mL NGF) were detected by Cell counting kit-8 (CCK8) and transferase-mediated DUTP-biotin nick end labeling (TUNEL) staining, respectively. It is found that NGF ameliorated the decline of growth activity and the increase of apoptosis in arsenic-induced SCs. This remarkable biological effect that NGF inhibited the increase of Bax expression and the decrease of Bcl-2 expression in arsenic-induced SCs was also determined by western blot and Real-time PCR. Moreover, the decrease in transmembrane resistance (TEER) and the expression of tight junction proteins ZO-1 and occludin was mitigated in SCs induced by arsenic due to NGF treatment. In conclusion, the above results confirmed that NGF could ameliorate the injury effects of arsenic on testis, which might be related to the function of NGF to inhibit arsenic-induced SCs injury.

Neuronal Panx1 drives peripheral sensitization in experimental plantar inflammatory pain

BackgroundThe channel-forming protein Pannexin1 (Panx1) has been implicated in both human studies and animal models of chronic pain, but the underlying mechanisms remain incompletely understood.MethodsWild-type (WT, n = 24), global Panx1 KO (n = 24), neuron-specific Panx1 KO (n = 20), and glia-specific Panx1 KO (n = 20) mice were used in this study at Albert Einstein College of Medicine. The von Frey test was used to quantify pain sensitivity in these mice following complete Freund’s adjuvant (CFA) injection (7, 14, and 21 d). The qRT-PCR was employed to measure mRNA levels of Panx1, Panx2, Panx3, Cx43, Calhm1, and β-catenin. Laser scanning confocal microscopy imaging, Sholl analysis, and electrophysiology were utilized to evaluate the impact of Panx1 on neuronal excitability and morphology in Neuro2a and dorsal root ganglion neurons (DRGNs) in which Panx1 expression or function was manipulated. Ethidium bromide (EtBr) dye uptake assay and calcium imaging were employed to investigate the role of Panx1 in adenosine triphosphate (ATP) sensitivity. β-galactosidase (β-gal) staining was applied to determine the relative cellular expression levels of Panx1 in trigeminal ganglia (TG) and DRG of transgenic mice.ResultsGlobal or neuron-specific Panx1 deletion markedly decreased pain thresholds after CFA stimuli (7, 14, and 21 d; P < 0.01 vs. WT group), indicating that Panx1 was positively correlated with pain sensitivity. In Neuro2a, global Panx1 deletion dramatically reduced neurite extension and inward currents compared to the WT group (P < 0.05), revealing that Panx1 enhanced neurogenesis and excitability. Similarly, global Panx1 deletion significantly suppressed Wnt/β-catenin dependent DRG neurogenesis following 5 d of nerve growth factor (NGF) treatment (P < 0.01 vs. WT group). Moreover, Panx1 channels enhanced DRG neuron response to ATP after CFA injection (P < 0.01 vs. Panx1 KO group). Furthermore, ATP release increased Ca2+ responses in DRGNs and satellite glial cells surrounding them following 7 d of CFA treatment (P < 0.01 vs. Panx1 KO group), suggesting that Panx1 in glia also impacts exaggerated neuronal excitability. Interestingly, neuron-specific Panx1 deletion was found to markedly reduce differentiation in cultured DRGNs, as evidenced by stunted neurite outgrowth (P < 0.05 vs. Panx1 KO group; P < 0.01 vs. WT group or GFAP-Cre group), blunted activation of Wnt/β-catenin signaling (P < 0.01 vs. WT, Panx1 KO and GFAP-Cre groups), and diminished cell excitability (P < 0.01 vs. GFAP-Cre group) and response to ATP stimulation (P < 0.01 vs. WT group). Analysis of β-gal staining showed that cellular expression levels of Panx1 in neurons are significantly higher (2.5-fold increase) in the DRG than in the TG.ConclusionsThe present study revealed that neuronal Panx1 is a prominent driver of peripheral sensitivity in the setting of inflammatory pain through cell-autonomous effects on neuronal excitability. This hyperexcitability dependence on neuronal Panx1 contrasts with inflammatory orofacial pain, where similar studies revealed a prominent role for glial Panx1. The apparent differences in Panx1 expression in neuronal and non-neuronal TG and DRG cells are likely responsible for the distinct impact of these cell types in the two pain models.

MSC-derived exosomes deliver ZBTB4 to mediate transcriptional repression of ITIH3 in astrocytes in spinal cord injury

BackgroundBMSC-secreted exosomes (BMSC-Exos) have shown potential for promoting behavioral recovery following spinal cord injury (SCI). However, its role in blocking astrocyte activation remains unclear. Thus, this study aimed to determine whether BMSC-Exos impair the function of astrocytes following SCI in mice and to seek the mechanism. MethodsBMSC-Exos were collected by ultracentrifugation and identified. The SCI mice were developed by laminectomy combined with spinal cord shock, followed by BMSC-Exos or nerve growth factor (positive control) treatment. HE staining, Nissl staining, and TUNEL were conducted to analyze the pathological structural damage and neuronal damage in the mouse spinal cord. Bioinformatics was used to screen altered molecules under the BMSC-Exos treatment. Effects of BMSC-Exos and changes in ZBTB4 and ITIH3 expression on neuronal damage induced by activated astrocytes in the co-culture system were analyzed by CCK-8 and flow cytometry. ResultsNerve growth factor and BMSC-Exos promoted motor function recovery, alleviated nerve injury, and reduced apoptosis in mice with SCI. ZBTB4 was enriched in BMSC-Exos and lowly expressed in SCI. Downregulation of ZBTB4 diminished the therapeutic effects of BMSC-Exos against SCI. ITIH3 was a downstream target of ZBTB4. Neurotoxic activation of astrocytes induced neuronal injury, which was alleviated by BMSC-Exos. However, ZBTB4 knockdown overturned the effects of BMSC-Exos in vitro and combined ITIH3 knockdown alleviated the accentuating effects of ZBTB4 knockdown on neuronal injury. ConclusionBMSC-Exos protected against astrocyte-induced neuronal injury by delivering ZBTB4 to repress ITIH3, ultimately improving motor function in mice with SCI.

Targeting Molecular Mechanisms of Obesity- and Type 2 Diabetes Mellitus-Induced Skeletal Muscle Atrophy with Nerve Growth Factor.

Skeletal muscle plays a critical role in metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Muscle atrophy, characterized by a decrease in muscle mass and function, occurs due to an imbalance between the rates of muscle protein synthesis and degradation. This study aimed to investigate the molecular mechanisms that lead to muscle atrophy in obese and T2DM mouse models. Additionally, the effect of nerve growth factor (NGF) on the protein synthesis and degradation pathways was examined. Male mice were divided into three groups: a control group that was fed a standard chow diet, and two experimental groups that were fed a Western diet. After 8 weeks, the diabetic group was injected with streptozotocin to induce T2DM. Each group was then further divided into NGF-treated or non-treated control group. In the gastrocnemius muscles of the Western diet group, increased expressions of myostatin, autophagy markers, and ubiquitin ligases were observed. Skeletal muscle tissue morphology indicated signs of muscle atrophy in both obese and diabetic mice. The NGF-treated group showed a prominent decrease in the protein levels of myostatin and autophagy markers. Furthermore, the NGF-treated group showed an increased Cyclin D1 level. Western diet-induced obesity and T2DM may be linked to muscle atrophy through upregulation of myostatin and subsequent increase in the ubiquitin and autophagy systems. Moreover, NGF treatment may improve muscle protein synthesis and cell cycling.

Effect of Specific mode electroacupuncture stimulation combined with NGF during the ischaemic stroke: Study protocol for a randomized controlled trial

BackgroundThe emergence of the Nerve Growth Factor (NGF) has promoted the development of neuroprotective therapy; however, it has little effect on cerebral ischemia because of its poor Blood-Brain Barrier (BBB) permeability. Specific Mode Electroacupuncture Stimulation (SMES) can open BBB safely and effectively; however, it has shown inconclusive clinical effects and indirect clinical evidence in the recovery phase. Hence, the authors conducted a multicentre, randomized, placebo-controlled, assessor-blinded clinical trial to assess the effectiveness and safety of SMES combined with NGF treatment used during ischaemic stroke recovery. MethodsA total of 288 stroke patients from three hospitals will be recruited and randomly allocated to four groups: acupuncture + placebo, acupuncture + NGF, SMES + placebo, and SMES + NGF, in a 1:1:1:1 ratio. Assessment data will be collected at baseline, 2-weeks, and 4-weeks during the treatment period, as well as at the 4-week and 8-week follow-up after treatment completion. The primary outcome measure will be the basic cure rate. The secondary outcome measures include the simplified Modified Barthel Index, Timed Up and Go Test, Fugl-Meyer Assessment of Motor Function Score, Tinetti Performance Oriented Mobility Assessment, Montreal Cognitive Assessment, and Loewenstein Occupational Therapy Cognitive Assessment. Moreover, resting-state functional magnetic resonance imaging and Functional near-infrared spectroscopy can detect changes in cerebral blood flow and brain function and investigate the relationship between the clinical efficacy and mechanism of the prescribed interventions. ConclusionThis study will provide clinical evidence for the efficacy and safety of SMES combined with NGF in the treatment of stroke patients.

Corneal Superficial Plaque Formation After Recombinant Human Nerve Growth Factor Use in a Patient With Neurotrophic Keratopathy and Limbal Stem Cell Deficiency From Mucous Membrane Pemphigoid.

The aim of this study was to report a rare observation of corneal superficial plaque formation after topical recombinant human nerve growth factor (rhNGF) treatment for a nonhealing epithelial defect in a patient with advanced mucous membrane pemphigoid, limbal stem cell deficiency, and neurotrophic keratopathy. This study was a case report. A 72-year-old man with a complex course of mucous membrane pemphigoid, leading to cicatrizing keratoconjunctivits, limbal stem cell deficiency, and neurotrophic keratopathy presented with a recurrent persistent epithelial defect in the right eye. After a long course of unsuccessful epithelial healing, despite various treatment modalities, he was administered topical rhNGF (cenegermin 0.002%; Oxervate, Dompé US Inc., Boston, MA) which successfully resolved the epithelial defect. However, on day 22 posttreatment, an unusual white, thick, adherent corneal superficial plaque formed. rhNGF was stopped and the plaque was carefully removed. Subsequently, there was no recurrence, and the patient's epithelial healing remained stable. Although the successful resolution of the persistent epithelial defect with rhNGF administration was notable, the development of the unusual epithelial overgrowth emphasizes the importance of vigilant monitoring and evaluation when using rhNGF in complex ocular conditions. Making informed decisions on the timing of discontinuing rhNGF can lead to desirable effects of the drug while mitigating additional side effects when managing such challenging cases.

Effect of recombinant human nerve growth factor treatment on corneal nerve regeneration in patients with neurotrophic keratopathy.

Neurotrophic Keratopathy (NK) is a neurodegenerative corneal disease that results in diminished corneal sensation. Previous studies have found that Cenegermin 0.002%, a recombinant human nerve growth factor (rhNGF), improves corneal epithelial healing in stage 2 and 3 NK patients. However, rhNGF effect on corneal sensation and nerve regeneration has not been well established. Thus, this study aims to analyze the effect of rhNGF on corneal nerve regeneration using in vivo confocal microscopy (IVCM) and on corneal sensitivity in NK patients. This is a retrospective, longitudinal, case-control study that included patients with NK, treated with rhNGF for at least 4 weeks, with pre- and post-treatment IVCM images available for analysis. Chart reviews were conducted documenting prior medical and surgical history, clinical signs and symptoms, and corneal sensation using Cochet-Bonnet esthesiometry. Corneal nerve parameters were assessed by IVCM. Sex- and age-matched reference controls were selected from a database of healthy subjects for comparison. The study included 25 patients, with 22 (88%) stage 1, two (8%) stage 2, and 1 (4%) stage 3 NK patients, with a median age of 64 years (range: 30-93 years). Total, main, and branch nerve densities [median (range) in mm/mm2] were lower in the NK group pre-treatment [2.3 (0.0-21.1); 1.7 (0.0-13.0); 0.5 (0.0-10.2); respectively] vs. controls [22.3 (14.9-29.0); 10.1 (3.2-15.4); and 12.1 (6.2-18.4), (p < 0.0001 for all), respectively]. Post-treatment nerve densities increased compared to pre-treatment to 5.3 (0.0-19.4, p = 0.0083) for total, 3.5 (0.0-13.2, p = 0.0059) for main, and 2.0 (0.0-10.4, p = 0.0251) for branch nerves, but remained lower than controls (p < 0.0001 for all). Corneal sensation increased from 2.3 ± 1.1 cm pre-treatment to 4.1 ± 1.4 cm post-treatment (p = 0.001). Median best corrected visual acuity significantly increased following rhNGF treatment from 0.4 (0.0-1.6) to 0.12 (-0.1 to 1.6) (p = 0.007). Patients with NK treated with at least 4 weeks of rhNGF, showed a significant increase in corneal nerve densities after treatment. A significant increase in corneal sensation, as well as best corrected visual acuity, was observed following treatment.

Induction of Cholinergic Phenotype in Mouse Neuroblastoma Cells Using Nerve Growth Factor

Nerve growth factor (NGF) is a key factor of neuronal differentiation. NGF plays an important role in growth and differentiation of sensory and sympathetic neurons in the peripheral nervous system. In the mature brain, NGF is important for the maintenance of a cholinergic neuronal phenotype. Here, we studied whether NGF is sufficient to induce cholinergic phenotype in murine neuroblastoma cells, which are often used to model various physiological and pathological conditions. We detected expression of both TrkA and p75NGFR of NGF receptors in NB41A3 and Neuro2a neuroblastoma cells, two the most popular cell lines widely used to study the properties of cholinergic neurons in vitro. Treatment of both types of cell cultures with NGF did not induce in contrast to 8-Br-cAMP, which induced differentiation of Neuro2a cells with formation neuron-like morphology. Furthermore, we did not reveal the markers of cholinergic phenotype, such as ChAT or VAChT mRNA or protein in these cells, after NGF treatment. Thus, NB41A3 and Neuro2a cells cannot be used as an in vitro model of cholinergic cells because they do not differentiate and/or exhibit cholinergic phenotype in response to NGF stimulation.

Analysis of Clinical Efficacy and Influencing Factors of Nerve Growth Factor (NGF) Treatment for Sudden Sensorineural Hearing Loss.

Objective: This study aims to examine the clinical efficacy and prognostic factors associated with nerve growth factor (NGF) treatment for sudden sensorineural hearing loss (SSHL). Materials and methods: A retrospective analysis was conducted on the clinical data of 101 patients with moderate or more severe SSHL who underwent secondary treatment at Sun Yat-sen Memorial Hospital of Sun Yat-sen University between January 2019 and July 2020. Prior to treatment, all patients were assessed using Pure Tone Audiometry (PTA), auditory brainstem response, otoacoustic emission, temporal bone computed tomography, or inner ear magnetic resonance imaging. Fifty-seven patients received conventional systemic treatment and served as the control group, while 44 patients received NGF in conjunction with conventional systemic treatment, forming the experimental group. PTA results were compared between the two groups before treatment and at 1 week, 2 weeks, and 1 month post-treatment. Additionally, the impact of age, sex, affected side, hypertension, and other factors on patient prognosis was analyzed. Results: Both groups demonstrated significant PTA improvements following treatment, with a statistically significant difference (P < .05). The hearing recovery effective rate in the control group was 42.1%, while that of the experimental group reached 70.5%, with a statistically significant difference between the groups (P < .05). Most patients experienced notable hearing improvements 1 week after treatment, with some patients still showing progress 2 weeks post-treatment. Multifactor analysis revealed that hypertension and onset days were associated with treatment outcomes. Conclusion: Secondary treatment remains clinically significant for patients with SSHL who have not achieved a satisfactory response or show no clear improvement following initial treatment. The presence of hypertension and delayed treatment are negative factors related to treatment efficacy.

Combined treatment of nerve growth factor and transcranical direct current stimulations to improve outcome in children with vegetative state after out-of-hospital cardiac arrest

BackgroundOut-of-hospital cardiac arrest (OHCA) is one of the most dramatic events in pediatric age and, despite advanced neurointensive care, the survival rate remains low. Currently, no effective treatments can restore neuronal loss or produce significant improvement in these patients. Nerve Growth Factor (NGF) is a neurotrophin potentially able to counteract many of the deleterious effects triggered by OHCA. Transcranial Direct Current Stimulation (tDCS) has been reported to be neuroprotective in many neurological diseases, such as motor deficit and cognitive impairment. Children with the diagnosis of chronic vegetative state after OHCA were enrolled. These patients underwent a combined treatment of intranasal administration of human recombinant NGF (hr-NGF), at a total dose of 50 gamma/kg, and tDCS, in which current intensity was increased from zero to 2 mA from the first 5 s of stimulation and maintained constant for 20 min. The treatment schedule was performed twice, at one month distance each. Neuroradiogical evaluation with Positron Emission Tomography scan (PET), Single Photon Emission Computed Tomography (SPECT), Electroencephalography (EEG) and Power Spectral Density of the brain (PSD) was determined before the treatment and one month after the end. Neurological assessment was deepened by using modified Ashworth Scale, Gross Motor Function Measure, and Disability Rating Scale.ResultsThree children with a chronic vegetative state secondary to OHCA were treated. The combined treatment with hr-NGF and tDCS improved functional (PET and SPECT) and electrophysiological (EEG and PSD) assessment. Also clinical conditions improved, mainly for the reduction of spasticity and with the acquisition of voluntary finger movements, improved facial mimicry and reaction to painful stimuli. No side effects were reported.ConclusionsThese promising preliminary results and the ease of administration of this treatment make it worthwhile to be investigated further, mainly in the early stages from OHCA and in patients with better baseline neurological conditions, in order to explore more thoroughly the benefits of this new approach on neuronal function recovery after OHCA.

Acute intranasal treatment with nerve growth factor limits the onset of traumatic brain injury in young rats.

Traumatic brain injury (TBI) comprises a primary injury directly induced by impact, which progresses into a secondary injury leading to neuroinflammation, reactive astrogliosis, and cognitive and motor damage. To date, treatment of TBI consists solely of palliative therapies that do not prevent and/or limit the outcomes of secondary damage and only stabilize the deficits. The neurotrophin, nerve growth factor (NGF), delivered to the brain parenchyma following intranasal application, could be a useful means of limiting or improving the outcomes of the secondary injury, as suggested by pre-clinical and clinical data. We evaluated the effect of acute intranasal treatment of young (20-postnatal day) rats, with NGF in a TBI model (weight drop/close head), aggravated by hypoxic complications. Immediately after the trauma, rats were intranasally treated with human recombinant NGF (50 μg·kg-1 ), and motor behavioural test, morphometric and biochemical assays were carried out 24 h later. Acute intranasal NGF prevented the onset of TBI-induced motor disabilities, and decreased reactive astrogliosis, microglial activation and IL-1β content, which after TBI develops to the same extent in the impact zone and the hypothalamus. Intranasal application of NGF was effective in decreasing the motor dysfunction and neuroinflammation in the brain of young rats in our model of TBI. This work forms an initial pre-clinical evaluation of the potential of early intranasal NGF treatment in preventing and limiting the disabling outcomes of TBI, a clinical condition that remains one of the unsolved problems of paediatric neurology.

Intranasal nerve growth factor for prevention and recovery of the outcomes of traumatic brain injury.

Traumatic brain injury is one of the main causes of mortality and disability worldwide. Traumatic brain injury is characterized by a primary injury directly induced by the impact, which progresses into a secondary injury that leads to cellular and metabolic damages, starting in the first few hours and days after primary mechanical injury. To date, traumatic brain injury is not targetable by therapies aimed at preventing and/or limiting the outcomes of secondary damage but only by palliative therapies. Nerve growth factor is a neurotrophin targeting neuronal and non-neuronal cells, potentially useful in preventing/limiting the outcomes of secondary damage in traumatic brain injury. This potential has further increased in the last two decades since the possibility of reaching neurotrophin targets in the brain through its intranasal delivery has been exploited. Indeed, molecules intranasally delivered to the brain parenchyma may easily bypass the blood-brain barrier and reach their therapeutic targets in the brain, with favorable kinetics, dynamics, and safety profile. In the first part of this review, we aimed to report the traumatic brain injury-induced dysfunctional mechanisms that may benefit from nerve growth factor treatment. In the second part, we then exposed the experimental evidence relating to the action of nerve growth factor (both in vitro and in vivo, after administration routes other than intranasal) on some of these mechanisms. In the last part of the work, we, therefore, discussed the few manuscripts that analyze the effects of treatment with nerve growth factor, intranasally delivered to the brain parenchyma, on the outcomes of traumatic brain injury.

Effect of Autologous Platelet-Rich Plasma Drops in the Treatment of Ocular Surface Disease.

Platelet rich plasma (PRP) is an autologous preparation that concentrates platelets in a small volume of plasma. The purpose of this study was to determine if PRP eye drops improved the symptoms and signs of ocular surface disease. A retrospective case series was conducted of patients who were prescribed PRP eye drops. Subjects were excluded if they did not have follow-up, underwent intraocular surgery prior to follow-up, received nerve growth factor treatments, or did not have a baseline examination with photography. Symptoms were assessed using the Ocular Surface Disease Index (OSDI). Patients also underwent a slit lamp exam, ocular surface staining with fluorescein and lissamine green, and Schirmer testing. The charts of 47 patients treated with PRP drops for ocular surface disease were reviewed. Sixty-four eyes of 32 patients were included in the study who had photographs of lissamine green staining taken at baseline and at follow-up. Thirteen patients (28%) had ocular graft-versus-host disease, 16 patients (34%) had Sjögren's syndrome, and 4 patients (8.5%) had rheumatoid arthritis. There was a statistically significant decrease in OSDI score from baseline to follow-up (39.5 vs 30.8 points, p = 0.02). Among the 64 eyes included, 9 (14%) had an improvement in conjunctival lissamine green staining, while 6 (9%) had an increase in staining at follow-up. Among the 20 eyes with Schirmer testing, there was a borderline significant increase in score from baseline to follow-up (5.9 vs 9.7, p = 0.06). Among the 44 eyes that had corneal fluorescein staining (CFS) reported, 8 (18.2%) had decreased staining and 2 (4.5%) had increased staining at follow-up. Treatment with PRP drops was associated with a significant improvement in symptoms in patients with ocular surface disease. Future larger prospective studies are needed to further evaluate the efficacy of PRP drops for treating ocular surface disease.

Effects of NGF and Photobiomodulation Therapy on Crush Nerve Injury and Fracture Healing: A Stereological and Histopathological Study in an Animal Model.

A stereological and histopathological study in an animal model. This study explores the effects of the nerve growth factor and photobiomodulation therapy on the damaged nerve tissue and fracture healing. A total of 24 rabbits were divided into 4 groups: control group (n = 5), nerve growth factor (NGF) group (n = 7), photobiomodulation (PBMT) group (n = 6), and nerve growth factor and photobiomodulation therapy (NGF+PBMT) group (n = 6). The vertical fracture was performed between the mental foramen and the first premolar, and the mental nerve was crushed for 30 seconds with a standard serrated clamp with a force of approximately 50N in all groups. The control group received an isotonic solution (.02mL, .09% NaCl) to the operation site locally. The NGF group received 1μg human NGF-β/.9% .2mL NaCl solution for 7 days locally. The PBMT group received PBMT treatment (GaAlAs laser, 810nm, .3W, 18J/cm2) every 48 hours for 14 sessions following the surgery. The NGF+PBMT group received both NGF and PBMT treatment as described above. After 28 days, the bone tissues and mental nerves from all groups were harvested and histologically and stereologically analyzed. According to the stereological results, the volume of the new vessel and the volume of the new bone were significantly higher in the PBMT group than in other groups (P < .001). According to the histopathological examinations, higher myelinated axons were observed in experimental groups than in the control group. As a result, PBMT has beneficial effects on bone regeneration. Based on the light microscopic evaluation, more regenerated axon populations were observed in the NGF group than in the PBMT and PBMT + NGF groups in terms of myelinated axon content.

Differentially expressed long noncoding RNAs and mRNAs in PC12 cells under lysophosphatidylcholine stimulation

Lysophosphatidylcholine (LPC) was previously found to show neuroprotective effect on nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) induced signalings. Also, numerous studies reported the emerging roles of long noncoding RNAs (LncRNAs) involved in neurodegenerative disease. However, the biological mechanism of LPC and expression profile of lncRNAs has not been reported. Here, lncRNAs in PC12 cells under LPC and NGF treatment were analyzed using high throughput sequencing technology for the first time. We identified 564 annotated and 1077 novel lncRNAs in PC12 cells. Among them, 121 lncRNAs were differentially expressed in the PC12 cells under LPC stimulation. KEGG analysis showed that differentially expressed mRNAs co-expressed with lncRNAs mainly enriched in ribosome, oxidative phosphorylation, Parkinson’s disease, Huntington’s disease and Alzheimer’s disease etc. LncRNA-mRNA network analysis showed that lncRNA ENSRNOT00000082515 had interactions with 626 different mRNAs suggesting that lncRNA ENSRNOT00000082515 probably play vital role. Finally, sequencing data were validated by qRT-PCR for ENSRNOT00000084874, ENSRNOT00000082515, LNC_001033 forward Fgf18, Vcam1, and Pck2.

NGF regulates sertoli cell growth and prevents LPS-induced junction protein damage via PI3K/AKT/NFκB signaling

Damage to Sertoli cell junction proteins caused by inflammation can lead to male infertility. Nerve growth factor (NGF) plays an important role in reproductive and inflammatory disease; however, whether and how NGF regulates Sertoli cell function remains unclear. Here, we aimed to assess the effect of NGF on the growth of Sertoli cells isolated from the testes of dairy goats and evaluate if NGF has a protective effect on these cells. We confirmed that Sertoli cell viability, proliferation, and ATP content increased following NGF treatment. In addition, qPCR results suggested that Sertoli cell apoptosis was inhibited after NGF treatment. To investigate the protective effect of NGF on Sertoli cells under pathological inflammatory conditions, LPS was used to induce inflammatory response in Sertoli cells. Post-treatment, the entangled filamentous pseudopodia of the cells loosened and no longer spanned adjacent cells. The expression of several junction proteins (ZO-1, occludin, CX-43, β-catenin, and N-cadherin), which was down-regulated after inflammatory response induction, was restored following NGF treatment. LPS-induced changes in cytotoxicity and transepithelial electrical resistance were reversed and the intercellular connections became tighter after NGF treatment. We further demonstrated that NGF prevented the inflammatory response of Sertoli cells via the PI3K/AKT/NFκB signaling pathway, similar to the effect of the PI3K-inhibitor, LY294002, which is modified by the PI3K activator, 740Y–P. These results provide insights for devising strategies for protecting the male reproductive system and curing or preventing associated pathological conditions.

Evaluation of clinical and histological effects of KGF-2 and NGF on corneal wound healing in an experimental alkali burn rabbit model

Endogenously produced peptide growth factors such as keratinocyte growth factor-2 (KGF-2) and nerve growth factor (NGF) play a key role in the natural corneal wound healing process. However, this self-healing ability of the corneal tissue is often impaired in cases of severe corneal damage, as in corneal alkali injuries. In the present study, we investigated the clinical and histopathological effects of topical recombinant human keratinocyte growth factor-2 and nerve growth factor treatments in a rabbit model of corneal alkali burn. After induction of an alkali burn, 24 rabbits were divided equally into three groups: control group, KGF-2 group, and NGF group. Clinical parameters including epithelial healing, opacification, neovascularization and central corneal thickness were evaluated on the first (D1), seventh (D7) and fourteenth (D14) days after injury. Corneal histology was performed using hematoxylin/eosin (H&E) and Masson's Trichrome stains. Immunohistochemical staining for matrix metalloproteinase-2 (MMP-2), MMP-9 and transforming growth factor-β (TGF-β) was performed. On D14, the percentage of epithelial defect and opacity were significantly less in the KGF-2 and NGF groups compared to the control group (p < 0.05). There was no significant difference between the groups in central corneal thickness. In the evaluation of neovascularization on D14, the NGF group was significantly less vascularized than the control group (p = 0.011). Histological examination showed a significant increase in stromal edema and inflammation in the control group compared to both treatment groups (p < 0.05). There was also a significant difference between the NGF and control groups in histological evaluation of epithelial repair and vascularization (p < 0.05). When immunoreactivity of MMP-2, MMP-9 and TGF-β was examined, there was a significant increase in the control group compared to the NGF group (p < 0.05). Taken together, both NGF and KGF-2 treatments were effective for early re-epithelialization and decrease in inflammation, opacity and neovascularization after corneal alkali burn. The inhibitory effect of NGF treatment on chemical-induced neovascularization was found to be superior to KGF-2 treatment.

Effect of Coriander on H2O2-induced Oxidative Stress in PC12 Cells

Objective: Coriander (Coriandrum sativum), a member of the Apiaceae family of plants, is traditionally used as a spice and medicinal plant which has anti-aging, anti-inflammatory, and anti-anxiety effects and is used for the treatment of diabetes. The present study aimed to investigate the effects of coriander on H2O2-induced neurotoxicity in PC12 cells. Methods: PC12 cells were cultured in Dulbecco’s modified Eagle’s medium, and the effects of various treatments were analyzed using cytotoxicity assay, morphological evaluation of neurite outgrowth, and western blotting. Results: The cytotoxicity assay showed increased levels of LDH in cells treated above 10-5 M H2O2, however there was no significant change in the coriander administration group. Morphological evaluation showed significantly increased neurite outgrowth in the nerve growth factor (NGF) treatment group after 72 h. Treatment of NGF-stimulated cells with H2O2 reversed the effect of NGF on neurite outgrowth, which returned to the levels of the control group. Simultaneous administration of H2O2, NGF and 0.1 or 0.01 µg/mL of coriander significantly increased neurite outgrowth after 72 h. Western blot showed that phosphorylated ERK levels were significantly increased in the NGF group compared with H2O2+NGF group, and no significant differences were found compared to the H2O2+NGF+0.1 µg/mL coriander administration group. Conclusion: Coriander reversed the reduction in neurite outgrowth following treatment of NGF-stimulated PC12 cells with H2O2. This suggests that coriander may help prevent oxidative stress-induced neurodegeneration.

Long-Term Intranasal Nerve Growth Factor Treatment Favors Neuron Formation in de novo Brain Tissue.

ObjectiveTo date, no safe and effective pharmacological treatment has been clinically validated for improving post-stroke neurogenesis. Growth factors are good candidates but low safety has limited their application in the clinic. An additional restraint is the delivery route. Intranasal delivery presents many advantages.Materials and MethodsA brain lesion was induced in twenty-four rats. Nerve growth factor (NGF) 5 μg/kg/day or vehicle was given intranasally from day 10 post-lesion for two periods of five weeks, separated by a two-week wash out period with no treatment. Lesion volume and atrophy were identified by magnetic resonance imaging (MRI). Anxiety and sensorimotor recovery were measured by behavior tests. Neurogenesis, angiogenesis and inflammation were evaluated by histology at 12 weeks.ResultsRemarkable neurogenesis occurred and was visible at the second and third months after the insult. Tissue reconstruction was clearly detected by T2 weighted MRI at 8 and 12 weeks post-lesion and confirmed by histology. In the new tissue (8.1% of the lesion in the NGF group vs. 2.4%, in the control group at 12 weeks), NGF significantly increased the percentage of mature neurons (19% vs. 7%). Angiogenesis and inflammation were not different in the two groups. Sensorimotor recovery was neither improved nor hampered by NGF during the first period of treatment, but NGF treatment limited motor recovery in the second period.InterpretationThe first five-week period of treatment was very well tolerated. This study is the first presenting the effects of a long treatment with NGF and has shown an important tissue regeneration rate at 8 and 12 weeks post-injury. NGF may have increased neuronal differentiation and survival and favored neurogenesis and neuron survival through subventricular zone (SVZ) neurogenesis or reprogramming of reactive astrocytes. For the first time, we evidenced a MRI biomarker of neurogenesis and tissue reconstruction with T2 and diffusion weighted imaging.