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Postherpetic pain (PHP) is difficult to control. Although Neurotropin® (NTP) and methylcobalamin (MCB) are often prescribed to treat the pain, the efficacy of combined treatment for PHP remains imcompletely understood. In this study, we investigate the combined effects of NTP and MCB on PHP in mice. NTP and MCB were administered from day 10–29 after herpes simplex virus type-1 (HSV-1) infection. The pain-related responses were evaluated using a paint brush. The expression of neuropathy-related factor (ATF3) and nerve repair factors (GAP-43 and SPRR1A) in the dorsal root ganglion (DRG) and neurons in the skin were evaluated by immunohistochemical staining. Nerve growth factor (NGF) and neurotrophin-3 (NT3) mRNA expression levels were evaluated using real-time PCR. Repeated treatment with NTP and MCB after the acute phase inhibited PHP. Combined treatment with these drugs inhibited PHP at an earlier stage than either treatment alone. In the DRG of HSV-1-infected mice, MCB, but not NTP, decreased the number of cells expressing ATF3 and increased the number of cells expressing GAP-43- and SPRR1A. In addition, MCB, but not NTP, also increased and recovered non-myelinated neurons decreased in the lesional skin. NTP increased the mRNA levels of NTF3 in keratinocytes, while MCB increased that of NGF in Schwann cells. These results suggest that combined treatment with NTP and MCB is useful for the treatment of PHP. The combined effect may be attributed to the different analgesic mechanisms of these drugs. • Neurotropin® and methylcobalamin to postherpetic pain (PHP) were evaluated in mice. • Combined treatment with these drugs to PHP showed faster efficacy than either drug. • Methylcobalamin effected the expression of the factors on neuropathy or nerve repair. • These drugs induced the gene expression on neurotropic factors. • Combined treatment with these drugs is more effective to PHP than each drug alone. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries are common and serious conditions. The effect of Neurotropin® (NTP), a nonprotein extract derived from the inflamed skin of rabbits inoculated with vaccinia virus, on peripheral nerve regeneration has not been fully elucidated. However, it has analgesic properties via the activation of descending pain inhibitory systems. Therefore, the current study aimed to determine the effects of NTP on peripheral nerve regeneration. We examined axonal outgrowth of dorsal root ganglion (DRG) neurons using immunocytochemistry in vitro. In addition, nerve regeneration was evaluated functionally, electrophysiologically, and histologically in a rat sciatic nerve crush injury model in vivo. Furthermore, gene expression of neurotrophic factors in the injured sciatic nerves and DRGs was evaluated. In the dorsal root ganglion neurons in vitro , NTP promoted axonal outgrowth at a concentration of 10 mNU/mL. Moreover, the systemic administration of NTP contributed to the recovery of motor and sensory function at 2 weeks, and of sensory function, nerve conduction velocity, terminal latency, and axon-remyelination 4 weeks after sciatic nerve injury. In the gene expression assessment, insulin-like growth factor 1 and vascular endothelial growth factor expressions were increased in the injured sciatic nerve 2 days postoperatively. Therefore, NTP might be effective in not only treating chronic pain but also promoting peripheral nerve regeneration after injury. [ABSTRACT FROM AUTHOR]

Objective: Parkinsonian lumbago is usually caused by lesions of the thalamus or spinothalamocortical pathways. Decreased lumbago directly improved quality of life. Materials and Methods: We succeeded to treat Parkinsonian lumbago of elderly patients. Results: One patient could walk independently during outpatient care and enjoy ground golf, even though near 24 years have passed since the onset of Parkinson's disease (PD). Conclusion: Safe habits and hobbies for the elderly of whole-body exercise such as ground golf exercise habits, rehabilitation, medications and Neurotropin are suspected to be favorable for long-term prognosis of PD. [ABSTRACT FROM AUTHOR]

Abstract Purpose We compared the clinical effects of Neurotropin, limaprost alfadex, and a combination of both drugs for lumbar spinal stenosis (LSS) with low back pain (LBP). Methods We conducted a multicenter, randomized, active-controlled, open-label trial from March 2021 to May 2022. Participants were patients diagnosed with LSS by MRI and were randomly assigned to three groups: Neurotropin/limaprost combination (NL group), Neurotropin (N group), and limaprost group (L group). Participants received the drugs administered orally for 12 weeks, and each examination and observation was performed before any drug administration and every 2 weeks thereafter. We recorded age, sex, height, weight, duration of symptoms, intermittent claudication distance, level of stenosis in MRI, and concomitant analgesics as examination items in the trial period. Items measured during the trial were visual analog scale (VAS) score (mm) for LBP, leg pain and numbness, walking activity (walking speed, stride length), standing balance (3 m Timed Up-and-Go (TUG) Test results, Five Times Sit-to-Stand Test (FTSST) results), LBP/Quality of Life (QOL)-related scores (Oswestry Disability Index (ODI), Euro QOL 5-Dimensions 5-Level (EQ-5D-5L), Roland–Morris Disability Questionnaire (RDQ)), psychological factors (Pain catastrophizing scale (PCS) and Pain Self-Efficacy Questionnaire (PSEQ) scores), and adverse events. Each item was evaluated using changes at each visit (weeks 2–12) from baseline value before drug administration (week 0), and changes were considered significant when p

Purpose: We compared the clinical effects of Neurotropin, limaprost alfadex, and a combination of both drugs for lumbar spinal stenosis (LSS) with low back pain (LBP). Methods: We conducted a multicenter, randomized, active-controlled, open-label trial from March 2021 to May 2022. Participants were patients diagnosed with LSS by MRI and were randomly assigned to three groups: Neurotropin/limaprost combination (NL group), Neurotropin (N group), and limaprost group (L group). Participants received the drugs administered orally for 12 weeks, and each examination and observation was performed before any drug administration and every 2 weeks thereafter. We recorded age, sex, height, weight, duration of symptoms, intermittent claudication distance, level of stenosis in MRI, and concomitant analgesics as examination items in the trial period. Items measured during the trial were visual analog scale (VAS) score (mm) for LBP, leg pain and numbness, walking activity (walking speed, stride length), standing balance (3 m Timed Up-and-Go (TUG) Test results, Five Times Sit-to-Stand Test (FTSST) results), LBP/Quality of Life (QOL)-related scores (Oswestry Disability Index (ODI), Euro QOL 5-Dimensions 5-Level (EQ-5D-5L), Roland–Morris Disability Questionnaire (RDQ)), psychological factors (Pain catastrophizing scale (PCS) and Pain Self-Efficacy Questionnaire (PSEQ) scores), and adverse events. Each item was evaluated using changes at each visit (weeks 2–12) from baseline value before drug administration (week 0), and changes were considered significant when p < 0.05. Results: We included results from 64 patients in the present study; 24 were assigned to the NL group (mean age 71.2 years), 20 to the N group (mean age 76.2 years), and 20 to the L group (mean age 74.4 years). There were no significant differences between the three groups in patient characteristics, concomitant analgesics, or baseline VAS score, gait balance, or QOL-related scores (p ≥ 0.05). The VAS and leg pain scores were significantly improved in Group L, and LBP was improved significantly in Group N. QOL and ODI scores improved significantly in the NL and L groups, EQ-5D score improved significantly in the L group, and RDQ score improved significantly in all groups (p < 0.05). Psychological factor and PCS scores improved significantly in the NL and L groups (p < 0.05). Walking speed and stride length were improved significantly in the NL and N groups (p < 0.05). TUG/FTSST scores were improved significantly in all groups (p < 0.05). Leg pain VAS score was improved significantly (p < 0.05) in the L group compared with the NL group after 6 and 12 weeks of administration, and LBP VAS was improved significantly in the N group after 6 weeks compared with the NL group (p < 0.05). Walking speed was significantly improved in the NL group after 2 weeks compared with the N group and improved significantly in the NL group after 6 weeks (p < 0.05) compared with the L group. RDQ was decreased significantly in the L group compared with the NL group after 8 weeks (p < 0.05). Conclusions: Combined use of Neurotropin and limaprost showed an additional effect on walking speed compared with single drug administration. Neurotropin may contribute to the improvement of low back pain, walking speed/stride length, and standing balance. Trial Registration: Japan Registry of Clinical Trials (jRCTs031200282). [ABSTRACT FROM AUTHOR]

We aimed to examine the efficacy of combination therapies of Neurotropin® with tramadol and Neurotropin with mirogabalin for neuropathic pain management. A neuropathic pain model (L5 spinal nerve ligation model: L5-SNL) using male Wistar rats was generated through tight ligation of the left fifth lumbar nerve using silk sutures. Mechanical allodynia was assessed using the 50% paw withdrawal threshold. The combined antiallodynic effects were evaluated using isobolographic analyses. Small intestinal transit was evaluated using the charcoal meal test, and motor coordination using the rota-rod test. Neurotropin (50-200 NU/kg, p.o.), tramadol (7.5-60 mg/kg, p.o.), and mirogabalin (3-30 mg/kg, p.o.) showed a dose-dependent antiallodynic effect in L5-SNL rats. The combined antiallodynic effects of Neurotropin and tramadol were additive or synergistic, whereas those of Neurotropin and mirogabalin were additive. Neurotropin (100-400 NU/kg, p.o.) did not affect the small intestinal transit, whereas tramadol (30-100 mg/kg, p.o.) significantly inhibited it. Neurotropin (100-400 NU/kg, p.o.) did not affect the walking time, whereas mirogabalin (10-100 mg/kg, p.o.) significantly decreased it. Neurotropin dose-dependently ameliorated mechanical allodynia in rats, and combination therapy with Neurotropin-tramadol or Neurotropin-mirogabalin may alleviate neuropathic pain without aggravating the adverse effects of tramadol and mirogabalin., Competing Interests: Declaration of competing interest All authors are employees of Nippon Zoki Pharmaceutical Co., Ltd. The authors indicated no potential conflicts of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Objective(s): Clinically effective analgesia treatment for patients afflicted with osteocarcinoma lessens the intensity of pain. The midbrain periaqueductal gray (PAG) plays a critical role in pain modulation, and activation of P2X3 receptors in this region mediates pain processing. Neurotropin is a small molecule drug used for analgesic treatment of a number of chronic pain conditions. The present study aims at determining whether P2X3 receptor activation in PAG is responsible for the analgesic effect of neurotropin in rats with osteocarcinoma pain. Materials and Methods: The tibia of female Sprague-Dawley rats was inoculated with breast carcinoma cells to establish the osteocarcinoma pain model. The effects of intraperitoneal injection of 6, 12, and 18 neurotropin units (NU)/kg on pain threshold and receptor expression of P2X3 in the ventrolateral PAG (vlPAG) were assessed. The P2X3 receptor antagonist A-317491 (1.5 nmol/0.3 µl) was administered into vlPAG with a high-dose neurotropin (18 NU/kg) to determine the role of this receptor in the analgesic effect. Results: The pain thresholds of the rats with osteocarcinoma pain continuously decreased, whereas P2X3 receptor expression in vlPAG only slightly increased after osteocarcinoma cell inoculation. Neurotropin substantially elevated the pain threshold and P2X3 receptor expression in vlPAG in a dose-dependent manner. A-317491 microinjection into vlPAG significantly reduced the analgesic effects of neurotropin in the rats with osteocarcinoma pain.Conclusion: Through these findings, it is shown that vlPAG P2X3 receptor activation participates in neurotropin-mediated analgesia mechanism in osteocarcinoma pain.

Existing guidelines advocate an updated therapeutic algorithm for chronic neuropathic pain (NeP), but pharmacotherapeutic management should be individualized to pain phenotypes to achieve higher efficacy. This study was aimed to evaluate the efficacy of medications, based on NeP phenotypes, and to propose symptom-based pharmacotherapy. This retrospective study was enrolled 265 outpatients with chronic NeP related to spinal disorders. The patients were classified into three groups: spinal cord-related pain, radicular pain, and cauda equina syndrome. Data were obtained from patient-based questionnaires using Neuropathic Pain Symptom Inventory (NPSI) and the Brief Scale for Psychiatric Problems in Orthopaedic Patients, and from clinical information. The proportions of patients with ≥ 30% and ≥ 50% reduction in NPSI score for each pain subtype (spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia) and drugs were evaluated. The pain reduction rate was significantly lower in patients with spinal cord-related pain, especially for paresthesia/dysesthesia. For spinal cord-related pain, duloxetine and neurotropin had insufficient analgesic effects, whereas mirogabalin was the most effective. Pregabalin or mirogabalin for radicular pain and duloxetine for cauda equina syndrome are recommended in cases of insufficient analgesic effects with neurotropin. The findings could contribute to better strategies for symptom-based pharmacotherapeutic management. [ABSTRACT FROM AUTHOR]

Background/objective: Spinal cord injury (SCI) severely and irreversibly damages the central nervous system. Neurotropin (NTP), a nonprotein extract obtained from inflamed rabbit skin inoculated with vaccinia virus, is a drug that has been used for more than sixty years to alleviate neuropathic pain. It also reportedly exerts a neuroprotective role in peripheral nerves and in response to various central nervous system diseases, such as brain injury and Alzheimer disease. However, whether NTP promotes SCI recovery remains unknown. This study evaluated NTP's effects after SCI and explored its underlying mechanisms in a rat contusion model of SCI. Method: NTP was intraperitoneally administered to adult female Wistar rats subjected to contusion-induced SCI. Functional recovery was evaluated with behavioural scores and electrophysiological examinations. Tissue recovery was assessed with magnetic resonance imaging as well as histological staining with haematoxylin and eosin and Luxol Fast Blue. Neuronal survival and gliosis were observed after NeuN and glial fibrillary acidic protein immunofluorescence. Levels of apoptosis were demonstrated with TdT-mediated dUTP nick-end labeling (TUNEL) staining, Caspase-3 and B-cell lymphoma-2 (Bcl-2) Western blot, and Annexin V/propidium iodide flow cytometry. A protein antibody chip analysis was performed to evaluate the expression levels of 67 rat cytokines. Results: NTP treatment improved the hindlimb locomotor recovery of the injured animals as well as their electrophysiological outcomes after SCI. A dosage of 50 NTP units/kg was found to optimize the efficacy of NTP. Magnetic resonance imaging revealed that lesion sizes decreased after NTP treatment. The haematoxylin and eosin and Luxol Fast Blue staining showed significant increases in the amount of spared tissue. The NeuN and glial fibrillary acidic protein immunofluorescence revealed that NTP treatment increased neuronal survival and reduced gliosis in tissue samples obtained from the lesion's epicentre. That NTP inhibited apoptosis was confirmed by the decreased number of TUNEL-positive cells, level of Caspase-3 expression, and number of Annexin V/propidium iodide–positive cells, as well as the increased level of Bcl-2 expression. The protein array analysis identified 28 differentially expressed proteins in the NTP group, and the gene ontology (GO) analysis showed that the enriched differentially expressed proteins implicate janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathways. The expression levels of proinflammatory cytokines such as interleukin 6, thymus chemokine-1(TCK-1), and lipopolysaccharide-induced CXC chemokine (LIX) decreased after NTP treatment, whereas the levels of prorepair cytokine hepatocyte growth factor and adiponectin increased. Conclusion: Our research provides evidence that NTP can improve functional outcomes and alleviate secondary injury after SCI by inhibiting apoptosis and modulating cytokines. The translational potential of this article: The multicomponent NTP might have broad target spectra in SCI pathophysiology and halt the secondary injury cascade. As a safe drug that features sixty years of clinical use as an analgesic, translating this demonstrated efficacy of NTP to addressing SCI in human patients may potentially be accelerated.

Background: Local anesthetics often are used in rotator cuff tears as therapeutic tools, although some cases have reported that they have detrimental effects. Neurotropin (NTP) is used widely in Japan as a treatment for various chronic pain conditions and is shown to have protective effects on cartilage and nerve cells. In this study, we investigated the protective effect of NTP against lidocaine-induced cytotoxicity. Methods: Tenocytes from rotator cuff tendons were incubated with lidocaine, NTP, lidocaine with NTP, and a control medium. Cell viability was evaluated using the WST-8 assay. Cell apoptosis was detected via annexin V staining using flow cytometry. The expression of BCL-2 and cytochrome c, which are involved in the intrinsic mitochondrial pathway of apoptosis, was evaluated via Western blotting and immunohistochemical staining. Results: In the cell viability assay, lidocaine decreased cell viability in a dose-dependent manner, and NTP did not affect cell viability. Moreover, NTP significantly inhibited the cytotoxic effect of lidocaine. The flow cytometry analysis showed that lidocaine significantly induced apoptosis in tenocytes, and NTP considerably inhibited this lidocaine-induced apoptosis. Western blotting experiments showed that lidocaine decreased the protein expression of BCL-2, and that NTP conserved the expression of BCL-2, even when used with lidocaine. Immunohistochemical staining for cytochrome c showed that 0.1% lidocaine increased cytochrome c-positive cells, and NTP suppressed lidocaine- induced cytochrome c expression. Conclusions: NTP suppresses lidocaine-induced apoptosis of tenocytes by inhibiting the mitochondrial apoptotic pathway. Intra-articular/ bursal injection of NTP with lidocaine could protect tenocytes in rotator cuff tendons against lidocaine-induced apoptosis. [ABSTRACT FROM AUTHOR]

Repetitive magnetic stimulation is effective for treating posttraumatic neuropathies following spinal or axonal injury. Neurotropin is a potential treatment for nerve injuries like demyelinating diseases. This study sought to observe the effects of high-frequency repetitive magnetic stimulation, neurotropin and their combined use in the treatment of peripheral nerve injury in 32 adult male Sprague-Dawley rats. To create a sciatic nerve injury model, a 10 mm-nerve segment of the left sciatic nerve was cut and rotated through 180° and each end restored continuously with interrupted sutures. The rats were randomly divided into four groups. The control group received only a reversed autograft in the left sciatic nerve with no treatment. In the high-frequency repetitive magnetic stimulation group, peripheral high-frequency repetitive magnetic stimulation treatment (20 Hz, 20 min/d) was delivered for 10 consecutive days after auto-grafting. In the neurotropin group, neurotropin therapy (0.96 NU/kg per day) was administrated for 10 consecutive days after surgery. In the combined group, the combination of peripheral high-frequency repetitive magnetic stimulation (20 Hz, 20 min/d) and neurotropin (0.96 NU/kg per day) was given for 10 consecutive days after the operation. The Basso-Beattie-Bresnahan locomotor rating scale was used to assess the behavioral recovery of the injured nerve. The sciatic functional index was used to evaluate the recovery of motor functions. Toluidine blue staining was performed to determine the number of myelinated fibers in the distal and proximal grafts. Immunohistochemistry staining was used to detect the length of axons marked by neurofilament 200. Our results reveal that the Basso-Beattie-Bresnahan locomotor rating scale scores, sciatic functional index, the number of myelinated fibers in distal and proximal grafts were higher and axon lengths were longer in the high-frequency repetitive magnetic stimulation, neurotropin and combined groups compared with the control group. These measures were not significantly different among the high-frequency repetitive magnetic stimulation, neurotropin and combined groups. Therefore, our results suggest that peripheral high-frequency repetitive magnetic stimulation or neurotropin can promote the repair of injured sciatic nerves, but their combined use seems to offer no significant advantage. This study was approved by the Animal Ethics Committee of the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, China on December 23, 2014 (approval No. 2014keyan002-01).

Synaptic plasticity is known to play role in pathogenesis of schizophrenia. Cognitive impairment is one of the complications of schizophrenia, leading to poor quality of life. Matrix metalloprotease-9 (MMP-9) and neurotrophin-3 (NT-3) are markers of synaptic plasticity, widely investigated in neuropsychiatric disorders. The objective of the study was to investigate the levels of MMP-9 and NT-3 and their association with cognitive impairment in schizophrenia. 124 schizophrenia patients and 124 controls were enrolled in the study. MMP-9 and NT-3 were estimated in both the groups using ELISA. Cognition was assessed using Addenbrooke cognitive examination-III (ACE-III) and disease severity was assessed using PANSS. MMP-9 (p =.003) and NT −3 (p <.001) were found to be elevated in schizophrenia cases compared to controls. There was significant association of MMP-9 with fluency (r = −0.195, p =.030), language (r = −0.196, p =.029) and total ACE-III scores (r = −0.197, p =.029). Also we observed that MMP-9 increases the risk of cognitive impairment in schizophrenia patients (OR = 2.509, CI= 1.215 − 5.18, p =.013). MMP-9 and NT-3 are elevated in schizophrenia. MMP-9 was associated with fluency and language component of cognition and increases the risk of cognitive impairment in schizophrenia. [ABSTRACT FROM AUTHOR]

The accumulation of lipid droplets in the cytoplasm of hepatocytes, known as hepatic steatosis, is a hallmark of non-alcoholic fatty liver disease (NAFLD). Inhibiting hepatic steatosis is suggested to be a therapeutic strategy for NAFLD. The present study investigated the actions of Neurotropin (NTP), a drug used for chronic pain in Japan and China, on lipid accumulation in hepatocytes as a possible treatment for NAFLD. NTP inhibited lipid accumulation induced by palmitate and linoleate, the two major hepatotoxic free fatty acids found in NAFLD livers. An RNA sequencing analysis revealed that NTP altered the expression of mitochondrial genes. NTP ameliorated palmitate-and linoleate-induced mitochondrial dysfunction by reversing mitochondrial membrane potential, respiration, and β-oxidation, suppressing mitochondrial oxidative stress, and enhancing mitochondrial turnover. Moreover, NTP increased the phosphorylation of AMPK, a critical factor in the regulation of mitochondrial function, and induced PGC-1β expression. Inhibition of AMPK activity and PGC-1β expression diminished the anti-steatotic effect of NTP in hepatocytes. JNK inhibition could also be associated with NTP-mediated inhibition of lipid accumulation, but we did not find the association between AMPK and JNK. These results suggest that NTP inhibits lipid accumulation by maintaining mitochondrial function in hepatocytes via AMPK activation, or by inhibiting JNK. [ABSTRACT FROM AUTHOR]

Vascular dementia (VD) is the second most common cause of dementia after Alzheimer's disease. Neuroinflammation contributes to pathogenesis of VD. Neurotropin (NTP) is an analgesic that has been shown to suppress inflammation and neural repair. But its effects on VD are still unclear. Therefore, this study aimed to investigate the therapeutic effects and potential mechanisms of NTP in the VD model mice established by bilateral common carotid artery stenosis method. In VD mice, we found that NTP treatment increased cerebral blood flow by Laser speckle imaging, reduced neuron loss by Nissl, HE and immunochemistry staining, attenuated white matter damage by magnetic resonance imaging and ultrastructural damage by transmission electron microscope, improved cognitive functions by new object recognition test and three-chamber test, Y maze test and Morris water maze test, inhibited significantly glial activation by immunofluorescence methods, reduced the expression of TLR4, down-regulated expression of MyD88 and phosphorylation of NF-κB P65, decreased the levels of pro-inflammatory cytokines IL-1β, IL-6 and TNFα. Further, we showed that administration of a TLR4 inhibitor TAK242 had a similar effect to NTP, while the TLR4 agonist CRX-527 attenuated the effect of NTP in the VD mice. Collectively, our study suggested that NTP alleviates cognitive impairment by inhibiting TLR4/MyD88/NF-κB inflammation signaling pathway in the VD mice. Thus, NTP may be a promising therapeutic approach and a potential TLR4 inhibitor for VD. [Display omitted] • VD mice showed neuronal loss and glial activation. • NTP ameliorated cognitive impairment in VD mice, decreased white matter degeneration and reduced levels of pro-inflammatory cytokines. • TAK242 had a similar effect to NTP, while CRX-527 attenuated the effects of NTP in VD mice. [ABSTRACT FROM AUTHOR]

Early brain injury (EBI) is closely linked to the development of delayed cerebral ischemia and poor outcomes after aneurysmal subarachnoid hemorrhage (SAH). This study aimed to evaluate the neuroprotective effect of neurotropin on EBI in a murine model of SAH. Twenty-four C57BL/6N mice were treated with intraperitoneal injections of either saline or 2.4 units of neurotropin at 1 h after SAH induction and for 3 days consecutively. SAH was created by an endovascular perforation method. In addition to the assessment of cerebral infarction and survival rate, motor and neurocognitive functions were also measured after SAH. Compared to the saline control group, the neurotropin group showed better recovery from locomotive and neurological declines after SAH. The neurotropin group also showed lower rates of post-SAH acute cerebral infarction and better memory and route-learning scores (p < 0.05). Meanwhile, there was no significant between-group differences in the overall mortality, hemodynamic parameters, or body weights. In conclusion, post-event treatment with neurotropin could be protective against EBI, lowering the incidence of ischemia and improving some motor and neurocognitive functions after SAH.

Mengye Zhu,1,* Fuqing Zhou,2,* Lingchao Li,1 Qin Yin,3 Mizhen Qiu,1 Yong Zhang1 1Department of Pain Clinic, 2Department of Radiology, The First Affiliated Hospital of Nanchang University, Nanchang, 3Department of Pain Clinic, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Spinal cord injury (SCI) complicated by epidural anesthesia, though rare, can result in neuropathic pain. However, the treatment for this kind of life-altering injury remains a challenge. A 7-year-old girl was referred with dyskinesia and severe pain in her right lower extremity due to an accidental SCI following lumbar puncture. After treatment with analgesics such as gabapentin, mecobalamin, and dexamethasone/methylprednisolone for 1 week, the myodynamia had improved, but progressive pain persisted. After treatment with neurotropin, a gradual decrease in visual analog scale score from 7 to 0 was observed. We herein first describe that neurotropin produced sustained relief of pain induced by SCI. This case suggests that neurotropin might be a promising drug in treating pediatric neuropathic pain caused by SCI. Keywords: spinal cord injury, pain, neurotropin, children

Purpose: Ischemic–hypoxic insult leads to detrimental effects on multiple organs. The brain is especially vulnerable, and it is hard to regenerate once damaged. Currently, therapeutic options are very limited. Previous studies have reported neuroprotective effects of neurotropin, a non-protein extract derived from the inflamed skin of rabbits inoculated with vaccinia virus, using a murine model of peripheral nerve injury and cultured cell lines. However, whether neurotropin might have protective effects against brain injuries remains unclear. We, therefore, investigated the neuroprotective effect of neurotropin and possible underlying mechanisms, using a mouse model of hypoxic–ischemic brain injury. Methods: Hypoxic–ischemic brain injury was induced via a combination of the left common carotid artery occlusion and exposure to hypoxic environment (8% oxygen) in adult male C57BL/6 mice. Immediately following induction of hypoxia–ischemia, mice received either saline or 2.4 units of neurotropin. The survival rate, neurological function, infarct volume, and expression of inflammatory cytokines were evaluated. Results: Compared to the control group, the neurotropin group exhibited a significantly higher survival rate (100% vs. 62.5%, p < 0.05) and lower neurological deficit scores (1; 0–2 vs. 3; 0–5, median; range, p < 0.05) after the hypoxic–ischemic insult. The administration of neurotropin also reduced infarct volume (18.3 ± 5.1% vs. 38.3 ± 7.2%, p < 0.05) and mRNA expression of pro-inflammatory cytokines. Conclusions: The post-treatment with neurotropin improved survival and neurological outcomes after hypoxic–ischemic insult. Our results indicate that neurotropin has neuroprotective effects against hypoxic–ischemic brain injury by suppressing pro-inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Rationale: One approach to improving exposure therapy for anxiety disorders has focused on developing pharmacological adjuncts to enhance extinction, but these efforts have produced modest success in clinical trials. Understanding the factors that predict the efficacy of adjuncts will help to develop personalized treatments for anxiety.Objectives: We assessed whether individual differences in within-session extinction (fear reduction during extinction training) predict the extent to which the neurotrophin fibroblast growth factor-2 (FGF2) enhances extinction recall in rats.Methods: We re-analyzed data from five experiments that involved administering FGF2 immediately after extinction training; extinction recall was assessed the following day.Results: Regression analyses revealed that fear responses at the end, but not the start, of extinction training predicted extinction recall in FGF2- but not vehicle-treated rats. Comparisons between FGF2- and vehicle-treated rats that exhibited better or worse extinction recall (determined by a median split in freezing during extinction recall) confirmed that FGF2-treated rats exhibiting better extinction recall had significantly lower freezing at the end of extinction training relative to FGF2-treated rats exhibiting poorer extinction recall. In contrast, vehicle-treated rats did not differ in within-session extinction based on their performance at extinction recall. Finally, even when classified as having poorer extinction recall, FGF2-treated rats had stronger extinction recall than vehicle-treated rats.Conclusions: These results suggest that FGF2 may be most effective amongst rats that exhibit the lowest fear responses at the end of extinction training. Furthermore, FGF2 does not appear to exacerbate fear in rats that exhibit minimal fear reduction during extinction training. [ABSTRACT FROM AUTHOR]

Infected or damaged tissues release multiple “alert” molecules such as alarmins and damage-associated molecular patterns (DAMPs) that are recognized by innate immune receptors, and induce tissue inflammation, regeneration, and repair. Recently, an extract from inflamed rabbit skin inoculated with vaccinia virus (Neurotropin®, NTP) was found to induce infarct tolerance in mice receiving permanent ischemic attack to the middle cerebral artery. Likewise, we report herein that NTP prevented the neurite retraction in PC12 cells by nerve growth factor (NGF) deprivation. This effect was accompanied by interaction of Fyn with high-affinity NGF receptor TrkA. Sucrose density gradient subcellular fractionation of NTP-treated cells showed heretofore unidentified membrane fractions with a high-buoyant density containing Trk, B subunit of cholera toxin-bound ganglioside, flotillin-1 and Fyn. Additionally, these new membrane fractions also contained Toll-like receptor 4 (TLR4). Inhibition of TLR4 function by TAK-242 prevented the formation of these unidentified membrane fractions and suppressed neuroprotection by NTP. These observations indicate that NTP controls TrkA-mediated signaling through the formation of clusters of new membrane microdomains, thus providing a platform for crosstalk between neurotrophic and innate immune receptors. Neuroprotective mechanisms through the interaction with innate immune systems may provide novel mechanism for neuroprotection.

It is suggested that most cases of low back pain are related to degeneration of intervertebral discs. Disc degeneration is a chronic and progressive disease and the search for effective medical treatments continues. Neurotropin is widely used in Japan and China to treat low back pain and neck–shoulder–arm syndrome. The present study aimed to investigate the effect of Neurotropin on glycosaminoglycan synthesis in nucleus pulposus cells. Cultured human nucleus pulposus cells were treated with Neurotropin every second day for two weeks. Production of glycosaminoglycan was assessed using a dimethyl-methylene blue assay and PicoGreen was used to measure DNA content. Microarray analysis, real-time PCR, and western blotting were performed to assess the biological processes related to Neurotropin-stimulated glycosaminoglycan synthesis. The results showed that the level of glycosaminoglycan normalized to DNA content was significantly upregulated by the addition of Neurotropin. Gene expression profiling showed over two-fold upregulation of 697 genes in response to Neurotropin treatment. Among these genes, ontological analysis suggested significant implication of phosphatidylinositol 3-kinase signaling, and analysis focused on this pathway demonstrated marked upregulation of angiopoietin 1 and insulin-like growth factor 1. Activation of phosphorylation of the signal transducer protein AKT was detected by western blotting. Of the genes related to sulfated glycosaminoglycan synthesis, the greatest increase in mRNA levels was observed for chondroitin sulfate N-acetylgalactosaminyltransferase 1, an enzyme initiating synthesis of chondroitin sulfate side chains attached to a core protein of aggrecan, which is a predominant disc matrix component. These findings suggest that Neurotropin may activate the phosphatidylinositol 3-kinase–AKT pathway and stimulate glycosaminoglycan synthesis through upregulation of expression of mRNA for chondroitin sulfate N-acetylgalactosaminyltransferase 1. Because there was no cytotoxic cellular growth inhibition, Neurotropin treatment might offer an accessible therapeutic strategy for intervertebral disc degeneration. [ABSTRACT FROM AUTHOR]

Abstract: Pruritus is a condition in which itch occurs in the absence of apparent skin lesions. It is sometimes unresponsive to treatment with topical moisturizers and often is unresponsive to antihistamines. We evaluated the antipruritic effects of Neurotropin injections in patients with moisturizer‐ and antihistamine‐resistant pruritus. We monitored these patients by itch scores recorded in symptom diaries, as well as reports of quality of life (QOL). This study investigated both the efficacy and safety of Neurotropin injections using an open‐label study design. We enrolled 40 patients from six participating study sites. Of the 40 patients that were initially enrolled, six patients were ineligible, and ultimately, 33 were included for evaluation after one patient dropped out. Neurotropin was administered by subcutaneous injection to 22 patients and intravenous injection to 11 patients at a frequency of once per week. Compared to data collected during a one‐week observation period prior to treatment, after seven injections of Neurotropin, there was a significant improvement in the Shiratori symptom severity score and the visual analog scale (VAS) scores for itch symptoms, and the Dermatology Life Quality Index (DLQI) for quality of life. No new adverse events occurred during the period of investigation. A notable benefit to Neurotropin is that it can be used in patients with renal impairment and patients receiving dialysis therapy. Our results demonstrated that Neurotropin is effective in the treatment of moisturizer‐ and antihistamine‐resistant pruritus. [ABSTRACT FROM AUTHOR]

Neurotropin®(NTP), a non-protein extract of inflamed rabbit skin inoculated with vaccinia virus, is clinically used for the treatment of neuropathic pain in Japan and China, although its effect on peripheral nerve regeneration remains to be elucidated. The purpose of this study was to investigate the effects of NTP on Schwann cells (SCs) in vitro and in vivo, which play an important role in peripheral nerve regeneration. In SCs, NTP upregulated protein kinase B (AKT) activity and Krox20 and downregulated extracellular signal-regulated kinase1/2 activity under both growth and differentiation conditions, enhanced the expression of myelin basic protein and protein zero under the differentiation condition. In a co-culture of dorsal root ganglion neurons and SCs, NTP accelerated myelination of SCs. To further investigate the influence of NTP on SCs in vivo, lysophosphatidylcholine was injected into the rat sciatic nerve, leading to the focal demyelination. After demyelination, NTP was administered systemically with an osmotic pump for one week. NTP improved the ratio of myelinated axons and motor, sensory, and electrophysiological function. These findings reveal novel effects of NTP on SCs differentiation in vitro and in vivo, and indicate NTP as a promising treatment option for peripheral nerve injuries and demyelinating diseases. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) complicated by epidural anesthesia, though rare, can result in neuropathic pain. However, the treatment for this kind of life-altering injury remains a challenge. A 7-year-old girl was referred with dyskinesia and severe pain in her right lower extremity due to an accidental SCI following lumbar puncture. After treatment with analgesics such as gabapentin, mecobalamin, and dexamethasone/methylprednisolone for 1 week, the myodynamia had improved, but progressive pain persisted. After treatment with neurotropin, a gradual decrease in visual analog scale score from 7 to 0 was observed. We herein first describe that neurotropin produced sustained relief of pain induced by SCI. This case suggests that neurotropin might be a promising drug in treating pediatric neuropathic pain caused by SCI. [ABSTRACT FROM AUTHOR]

Aims The main purpose was to verify the potent capacity of Neurotropin® against neuronal damage in hippocampus and to explore its underlying mechanisms. Methods HT22 cells were treated with 40 μmol/L Aβ25-35 in the presence of various concentrations of Neurotropin® or in its absence. The cell viability was assessed with a CCK-8 assay, and flow cytometry was used to measure cell apoptosis, intracellular ROS levels, and mitochondrial membrane potential. Aβ plaques were examined by Bielschowsky silver staining, and the activities of antioxidants were detected in hippocampus of APP/ PS1 mice after Neurotropin® treatment. The expression of proteins, including HIF-1α, Bcl-2, Bax, and MAPKs signaling molecules was evaluated by Western blot. Results Neurotropin® significantly reversed the cell injury induced by Aβ25-35 through increasing cell viability and mitochondrial membrane potential, decreasing intracellular ROS and cell apoptosis of HT22 cells ( P<.05). Furthermore, Neurotropin® markedly reduced the formation of Aβ plaques and upregulated the activities of antioxidants ( P<.05). Additionally, the protein expression of HIF-1α, p- ERK1/2, p- JNK, and p-P38 was significantly inhibited in hippocampus of APP/ PS1 mice. Conclusions Neurotropin® exhibited a potent neuroprotective effect on inhibiting Aβ-induced oxidative damage and alleviating Aβ deposition in hippocampus via modulation of HIF-1α/ MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Aims Neurotropin® (NTP), an analgesic for chronic pain, has antihyperalgesic effects in specific alternation of rhythm in temperature (SART)-stressed rats. Previous studies have shown that SART stress induces hyperalgesia, as well as post-translational modification of proteins (including substrates for calpain, a calcium-dependent cysteine protease) in the mesencephalon of rats. To better understand the mechanism of action of NTP, we investigated whether SART stress activates calpain in the mesencephalon of rats and whether NTP inhibits this activation. Main methods Wistar rats were exposed to SART stress for 5 days. NTP (200 NU/kg/day) was administered intraperitoneally every day from the onset of SART stress. The mechanical pain threshold was measured using the Randall-Selitto test on the 6th day. Thereafter, the rat mesencephalon was immediately collected and calpain activity was examined using western blot analysis with a calpain cleavage site-specific antibody. Key findings SART stress induced hyperalgesia and increased the calpain activity in the mesencephalon of rats. In contrast, NTP treatment attenuated the hyperalgesia and prevented the increase in calpain activity in the mesencephalon of SART-stressed rats. Interestingly, a negative correlation was identified between calpain activity and mechanical pain threshold in SART-stressed rats treated with or without NTP. Furthermore, NTP inhibited calpain activity on mammalian uncoordinated-18 in rat mesencephalon homogenate and Ac-LLY-AFC as substrates in an in vitro cell-free system. Significance Our data demonstrate that NTP treatment prevents SART stress-induced calpain activation in the mesencephalon of rats and suggests that NTP-mediated antihyperalgesia is associated with an inhibition of calpain activity in the mesencephalon. [ABSTRACT FROM AUTHOR]

Neuropathic pain caused by nerve damage in the central and/or peripheral nervous systems is a refractory disorder and the management of such chronic pain has become a major issue. Neurotropin is a drug widely used in Japan and China to treat chronic pain. Although Neurotropin has been demonstrated to suppress chronic pain through the descending pain inhibitory system, the mechanism of analgesic action in the peripheral nervous system remains to be elucidated. In this study, we investigated the local effects of Neurotropin on peripheral nerve damage in a chronic constriction injury (CCI) model. Neurotropin reduced mRNA expressions of IL-1β, IL-6, and TNF-α in the sciatic nerve 1 day after the injury. Activation of Erk was also inhibited locally in the Neurotropin treatment group. Since Erk activation results in demyelination along with dedifferentiation of Schwann cells, we investigated the expression level of myelin basic protein. Five days after the injury, Neurotropin attenuated the downregulation of myelin basic protein in the sciatic nerve in the CCI model. Local effects of Neurotropin around the injury site may result in discovery of new treatments for not only neuropathic pain but also demyelinating diseases and peripheral nervous system injury. [ABSTRACT FROM AUTHOR]

This report presents our studies of the ATP-dependent and calcium mechanisms of the effects of salicylates on the electrical activity of neurons in the mollusk Helix albescens Rossm. Adenosine triphosphate (5·10 M) added simultaneously with salicylates in the extracellular medium significantly modified their neurotropic effects, eliminating the nonselective suppression of neuron spike activity by acetylsalicylic acid and increasing the activatory influences of cobalt and zinc acetylsalicylates. Blockade of uptake of Ca into the neuroplasm from the extracellular medium and intracellular depots with 5·10 M and 5·10 M CdCl and BaCl had no significant effect on neuron responses to salicylates, suggesting that calcium mechanisms are not involved. [ABSTRACT FROM AUTHOR]

Borna disease virus (BDV) is a non-segmented negative-stranded RNA virus that maintains a strictly neurotropic and persistent infection in affected end hosts. The primary target cells for BDV infection are brain cells, e.g. neurons and astrocytes. The exact mechanism of how infection is propagated between these cells and especially the role of the viral glycoprotein (GP) for cell-cell transmission, however, are still incompletely understood. Here, we use different cell culture systems, including rat primary astrocytes and mixed cultures of rat brain cells, to show that BDV primarily spreads through cell-cell contacts. We employ a highly stable and efficient peptidomimetic inhibitor to inhibit the furin-mediated processing of GP and demonstrate that cleaved and fusion-active GP is strictly necessary for the cell-to-cell spread of BDV. Together, our quantitative observations clarify the role of Borna disease virus-glycoprotein for viral dissemination and highlight the regulation of GP expression as a potential mechanism to limit viral spread and maintain persistence. These findings furthermore indicate that targeting host cell proteases might be a promising approach to inhibit viral GP activation and spread of infection. [ABSTRACT FROM AUTHOR]

New methods for synthesizing pyrano[3,4- b ]furo[2,3- b]pyridine derivatives from 7,7-dimethyl-2-oxo-3-cyano-1,2,7,8-tetrahydro-5 H-pyrano[4,3- b ]pyridine were developed. Their neurotropic activity was investigated. [ABSTRACT FROM AUTHOR]

Diagnosis of nervous necrosis virus (NNV) infection in susceptible fish species is mostly performed post-mortem due to the neurotropism of the causative agent and the only validated diagnostic assays require samples from brain and retinal tissue. However, a non-lethal alternative to test for exposure of fish to NNV is needed. An indirect ELISA for the detection of anti-NNV antibodies in was recently developed and evaluated to detect responses in the sera from immunized fish. For this study, we assessed the accuracy of the assay at detecting specific antibodies from naturally exposed fish using field samples from populations with differing infection status. We applied a Bayesian model, using RTqPCR as a second test. Median estimates of the diagnostic sensitivity and specificity of the VNN ELISA were 81.8% and 86.7%, respectively. We concluded that the assay was fit for the purpose of identifying animals in naturally exposed populations. With further evaluation in larger populations the test might be used to inform implementation of control measures, and for estimating infection prevalence to facilitate risk analysis. To our knowledge this is the first report on the diagnostic accuracy of an antibody ELISA for an infectious disease in finfish. [ABSTRACT FROM AUTHOR]

This investigation aimed to assess whether inhibition of cathecol-O-methyl transferase (COMT) by tolcapone could provide neuroprotection against HIV-associated neurodegenerative effects. This study was conducted based on a previous work, which showed that a single nucleotide polymorphism (SNP) at position 158 (val158met) in COMT, resulted in 40 % lower COMT activity. Importantly, this reduction confers a protective effect against HIV-associated neurocognitive disorders (HAND), which have been linked to HIV-associated brain changes. SH-SY5Y-differentiated neurons were exposed to macrophage-propagated HIV (neurotropic MACS2-Br strain) in the presence or absence of tolcapone for 6 days. RNA was extracted, and qPCR was performed using Qiagen RT2 custom array consisting of genes for neuronal and synaptic integrity, COMT and pro-inflammatory markers. Immunofluorescence was conducted to validate the gene expression changes at the protein level. Our findings demonstrated that HIV significantly increased the messenger RNA (mRNA) expression of COMT while reducing the expression of microtubule-associated protein 2 ( MAP2) ( p = 0.0015) and synaptophysin ( SYP) ( p = 0.012) compared to control. A concomitant exposure of tolcapone ameliorated the perturbed expression of MAP2 ( p = 0.009) and COMT ( p = 0.024) associated with HIV. Immunofluorescence revealed a trend reduction of SYP and MAP2 with exposure to HIV and that concomitant exposure of tolcapone increased SYP ( p = 0.016) compared to HIV alone. Our findings demonstrated in vitro that inhibition of COMT can ameliorate HIV-associated neurodegenerative changes that resulted in the decreased expression of the structural and synaptic components MAP2 and SYP. As HIV-associated dendritic and synaptic damage are contributors to HAND, inhibition of COMT may represent a potential strategy for attenuating or preventing some of the symptoms of HAND. [ABSTRACT FROM AUTHOR]

Aims Although the clinical use of Neurotropin ® as an analgesic for chronic pain has been firmly established, its analgesic mechanism is still unclear. In this study, we investigate the direct effects of Neurotropin using an electrophysiological method. Main methods Blind patch-clamp recordings were made from rat locus coeruleus (LC) and periaqueductal gray (PAG) neurons in brainstem slices of normal rats. The effects of intracerebroventricular (icv) injection of Neurotropin on nociceptive transmission were recorded from spinal substantia gelatinosa (SG) neurons in fifth lumbar spinal nerve-ligated (L5-SNL) rats using an in vivo patch-clamp method. Key findings Neurotropin (0.2–1.0 NU/mL) dose-dependently increased the firing rate in noradrenergic LC neurons of normal rats. Under the voltage-clamp condition, Neurotropin induced an inward current in 90% of LC neurons that was not affected by tetrodotoxin or an injection of GDP-β-S (G protein inhibitor) through recording pipettes. In contrast, Neurotropin had no effects on all PAG neurons tested. Using in vivo patch-clamp recordings, the icv injection of Neurotropin inhibited both frequency and amplitude of pinch-evoked excitatory postsynaptic currents of SG neurons in L5-SNL rats. These results suggest that Neurotropin directly excites the descending noradrenergic LC neurons and inhibits nociceptive transmission in the spinal dorsal horn. Significance This study is the first direct demonstration that Neurotropin activates the noradrenergic descending pain inhibitory systems, and this would reinforce the usefulness of Neurotropin in the treatment of human neuropathic pain. [ABSTRACT FROM AUTHOR]

Chronic pruritus is a major and distressing symptom of many cutaneous diseases, however, the treatment remains a challenge in the clinic. The traditional Chinese-Japanese medicine (Kampo medicine) is a conservative and increasingly popular approach to treat chronic pruritus for both patients and medical providers. Yokukansankachimpihange (YKH), a Kampo formula has been demonstrated to be effective in the treatment of itching of atopic dermatitis in Japan although its pharmacological mechanism is unknown clearly. In an attempt to clarify its pharmacological actions, in this study, we focused on the inhibitory activity of YKH against neurite growth induced with nerve growth factor (NGF) in cultured rat dorsal root ganglion (DRG) neurons because epidermal hyperinnervation is deeply related to itch sensitization. YKH showed approximately 200-fold inhibitory activity against NGF-induced neurite growth than that of neurotropin (positive control), a drug used clinically for treatment of chronic pruritus. Moreover, it also found that Uncaria hook, Bupleurum root and their chemical constituents rhynchophylline, hirsutine, and saikosaponin a, d showed inhibitory activities against NGF-induced neurite growth, suggesting they should mainly contribute to the inhibitory activity of YKH. Further study on the effects of YKH against epidermal nerve density in "itch-scratch" animal models is under investigation. [ABSTRACT FROM AUTHOR]

Neurotropin (NTP), a non-protein extract isolated from the inflamed skin of rabbits inoculated with vaccinia virus, is used clinically for the treatment of neuropathic pain. Moreover, NTP may activate the descending pain inhibitory system. Depression-like behavior is often complicated by chronic pain. However, little is known about NTP-mediated prevention of mood disorders in chronic pain and its molecular mechanisms. We aimed to investigate the effects of NTP on brain-derived neurotrophic factor (BDNF)-mediated signaling and gene expression in chronic pain. In addition, these effects of NTP were compared with pregabalin which is an anticonvulsant, anxiolytic analgesic used to treat neuropathic pain and fibromyalgia. A chronic constriction injury model was established in Sprague-Dawley rats. The pain response was assessed using a paw withdrawal latency (PWL) test and depression was assessed by the immobility time in a forced swim test (FST). NTP was orally administered in two doses of 50 NU (Neurotropin Unit) and 100 NU/kg for 7 days from day 7 after injury. To measure the analgesic and anti-depressant effects of NTP, either K252a (a tyrosine kinase inhibitor), or 5,7-dihydroxy tryptamine (5,7-DHT, a selective toxin for 5-HTergic neurons) was administered by intracerebroventricular injection. Changes in pERK1/2 and pCREB (immunohistochemistry), 5-HT, and BDNF protein level (ELISA) and BDNF mRNA (RT-PCR) were measured in the anterior cingulate cortex (ACC) and in the rostral ventromedial medulla (RVM) 14 days after injury. After injury, the rats showed a decrease in PWL associated with the increase in time of immobility in FST. In this injury model, NTP blocked both the decrease in PWL and the increase in the FST, while pregabalin (10 mg/kg, po.) did not affect the increase in the FST. These effects of NTP were reversed by K252a, and 5,7-DHT. The analgesic effects of pregabalin were not reversed by K252a. NTP normalized the injury-induced excessive activation of pERK1/2 associated with decreased pCREB and BDNF mRNA in the ACC and in the RVM, and these changes were reversed by 5,7-DHT. In contrast, pregabalin did not affect either pCREB or BDNF levels in the chronic pain model. NTP ameliorated chronic pain and pain-related depression by normalizing the induction of BDNF associated with the 5-HTergic system. Pregabalin showed the analgesic effects but had no effects on either depression or the BDNF pathway. These results suggest that NTP may represent an additional drug strategy for chronic pain associated with depression. [ABSTRACT FROM AUTHOR]

Activation of the high-affinity nerve growth factor (NGF) receptor Trk occurs through multiple processes consisted of translocation and clustering within the plasma membrane lipid rafts, dimerization and autophosphorylation. Here we found that a nonprotein extract of inflamed rabbit skin inoculated with vaccinia virus (Neurotropin ® ) enhanced efficiency of NGF signaling. In rat pheochromocytoma PC12 cells overexpressing Trk (PCtrk cells), Neurotropin augmented insufficient neurite outgrowth observed at suboptimal concentration of NGF (2 ng/mL) in a manner depending on Trk kinase activity. Cellular exposure to Neurotropin resulted in an accumulation of Trk-GM1 complexes without affecting dimerization or phosphorylation states of Trk. Following NGF stimulation, Neurotropin significantly facilitated the time course of NGF-induced Trk autophosphorylation. These observations provide a unique mechanism controlling efficiency of NGF signaling, and raise the therapeutic potential of Neurotropin for various neurological conditions associated with neurotrophin dysfunction. [ABSTRACT FROM AUTHOR]

Parkinsonism is a rare complication of encephalitis in childhood. Association to an isolated involvement of substantia nigra is exceptional. Mechanisms of nigral cells neurotropism remain hypothetic. We report on three children presenting with postencephalitic parkinsonism and selective involvement of substantia nigra, with literature review and we discuss pathogenic mechanisms. [ABSTRACT FROM AUTHOR]

A growing body of literature suggests that exposure to the neurotropic parasite Toxoplasma gondii ( T. gondii ) is associated with increased risk of mental disorders, particularly schizophrenia. However, a potential association between T. gondii exposure and anxiety disorders has not been rigorously explored. Here, we examine the association of T. gondii infection with both anxiety and mood disorders. Participants ( n = 484) were drawn from the Detroit Neighborhood Health Study, a population-representative sample of Detroit residents. Logistic regression was used to examine the associations between T. gondii exposure (defined by seropositivity and IgG antibody levels) and three mental disorders: generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD) and depression. We found that T. gondii seropositivity was associated with a 2 times greater odds of GAD (odds ratio (OR), 2.25; 95% confidence interval (CI), 1.11–4.53) after adjusting for age, gender, race, income, marital status, and medication. Individuals in the highest antibody level category had more than 3 times higher odds of GAD (OR, 3.35; 95% CI, 1.41–7.97). Neither T. gondii seropositivity nor IgG antibody levels was significantly associated with PTSD or depression. Our findings indicate that T. gondii infection is strongly and significantly associated with GAD. While prospective confirmation is needed, T. gondii infection may play a role in the development of GAD. [ABSTRACT FROM AUTHOR]

Inflammatory response and cell death in hepatocytes are hallmarks of chronic liver disease, and, therefore, can be effective therapeutic targets. Neurotropin® (NTP) is a drug widely used in Japan and China to treat chronic pain. Although NTP has been demonstrated to suppress chronic pain through the descending pain inhibitory system, the action mechanism of NTP remains elusive. We hypothesize that NTP functions to suppress inflammatory pathways, thereby attenuating disease progression. In the present study, we investigated whether NTP suppresses inflammatory signaling and cell death pathways induced by interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) in hepatocytes. NTP suppressed nuclear factor-κB (NF-κB) activation induced by IL-1β and TNFα assessed by using hepatocytes isolated from NF-κB-green fluorescent protein (GFP) reporter mice and an NF-κB-luciferase reporter system. The expression of NF-κB target genes, Il6, Nos2, Cxcl1, ccl5 and Cxcl2 induced by IL-1β and TNFα was suppressed after NTP treatment. We also found that NTP suppressed the JNK phosphorylation induced by IL-1β and TNFα. Because JNK activation contributes to hepatocyte death, we determined that NTP treatment suppressed hepatocyte death induced by IL-1β and TNFα in combination with actinomycin D. Taken together, our data demonstrate that NTP attenuates IL-1β and TNFα-mediated inflammatory cytokine expression and cell death in hepatocytes through the suppression of NF-κB and JNK. The results from the present study suggest that NTP may become a preventive or therapeutic strategy for alcoholic and non-alcoholic fatty liver disease in which NF-κB and JNK are thought to take part. [ABSTRACT FROM AUTHOR]

Objective: An 87-year-old female diagnosed with Parkinson's disease consulted our clinic presenting with gait disturbance and lumbago. Design: A clinical study. Materials and methods: The patient had hypokinesia, a stooped posture and walking with short steps. And in the "off" periods, slow movement, gait disturbance and lumbago became worse. She was diagnosed with Parkinson's disease at modified Hoehn & Yahr (HY) stage 4. The total unified Parkinson's disease rating scale (UPDRS) and revised version of Hasegawa's dementia scale (HDS-R) became 71 and 25 respectively. Results: Her visual analogue scale (VAS) score for lumbago was 52 mm on a 0-100 mm scale. We started the treatment with 624 mg/day of Neurotropin tablets. After treatment with Neurotropin, her lumbago dramatically improved. Conclusions: Neurotropin may be useful for the clinical management of lumbago of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Currently, chemotherapy and targeted therapies share the principal limitation of the emergence of drug resistance, which prevents these strategies from having lasting clinical benefits. The combination of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with concurrent chemotherapy has been proposed as one strategy to overcome acquired resistance to EGFR-TKIs. The purpose of the present study was to investigate the combined effects of gefitinib and pemetrexed on EGFR-TKI-sensitive and EGFR-TKI-resistant human non-small cell lung cancer (NSCLC) cell lines. The antiproliferative effects of gefitinib and pemetrexed, alone and in combination, on the growth of NSCLC cell lines, were assessed using an MTT assay. The cytotoxic interaction between the two drugs was evaluated in vitro using the combination index (CI) method. Cell cycle distribution and apoptosis were analyzed by flow cytometry and alterations in signaling pathways were determined by western blot analysis. In the present study, it was identified that when cells were concurrently exposed to pemetrexed and gefitinib, cytotoxic synergism was present in the gefitinib-resistant PC9/GR human NSCLC cell line and antagonistic interactions were observed in the gefitinib-sensitive PC9 cell line. Synergism was associated with a combination of cell cycle effects of the different agents. In addition, the combination of pemetrexed and gefitinib decreased the levels of phosphorylated AKT, phosphorylated extracellular-signal-regulated kinase and B-cell lymphoma 2 as compared with those in the control. By contrast, antagonism was associated with gefitinib-induced G0/G1-phase blockade of gefitinib-sensitive cells, which interfered with the cell cycle-specific cytotoxicity of chemotherapy. The combination of pemetrexed and gefitinib generated synergistic effects in gefitinib-acquired resistant cells and antagonistic effects in gefitinib-sensitive cells, suggesting that EGFR-TKIs combined with pemetrexed may be a beneficial treatment strategy for NSCLC patients with acquired resistance to EGFR-TKIs. [ABSTRACT FROM AUTHOR]

Highlights: [•] 11-mer peptide Lumbricusin, a defensin like peptide, is isolated from earthworm. [•] We here demonstrated that Lumbricusin has neurotropic and neuroprotective effects. [•] p27 degradation by Lumbricusin mediates effects of Lumbricusin on neuronal cells. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic peripheral neuropathies. We previously reported that repeated administration of neurotropin prevents oxaliplatin-induced mechanical allodynia by inhibiting axonal degeneration in rats. In the present study, we investigated the analgesic effect of a single administration of neurotropin on oxaliplatin-induced neuropathy in rats. Main methods: Oxaliplatin (4mg/kg) was administered intraperitoneally twice a week for 4weeks. Cold hyperalgesia was assessed using the acetone test and mechanical allodynia was evaluated using the von Frey test. Key findings: Repeated injection of oxaliplatin induced cold hyperalgesia on day 5 and mechanical allodynia on day 28. A single administration of neurotropin transiently relieved both pain behaviors. The analgesic effect of neurotropin was inhibited by pretreatment with 5-HT1A, 5-HT2, 5-HT3, and ?2 receptor antagonists and by monoamine depletion. Moreover, the analgesic effect of neurotropin was abolished by intrathecal injection of pertussis toxin, a Gi protein inhibitor. Significance: These results suggest that neurotropin is effective in relieving oxaliplatin-induced neuropathy, and that Gi protein-coupled receptors in the monoaminergic descending pain inhibitory system may be involved in the analgesic effect of neurotropin. Neurotropin may have clinical potential for the treatment of oxaliplatin-induced neuropathies. [Copyright &y& Elsevier]