MiR-210-5p promotes the differentiation of human induced pluripotent stem cells into dopaminergic neural precursors by targeting SMAD4 and SUFU and treats parkinsonian rats.

The differentiation of human induced pluripotent stem cells (hiPSCs) into functional dopaminergic neural precursors is the basis of cell therapy for Parkinson's disease (PD). However, the use of small molecule inhibitors/activators in the differentiation of hiPSCs in vitro leads to cell death and low differentiation efficiency. Moreover, the mechanism of differentiation remains unclear. MiR-210-5p was increased during hiPSCs differentiation. Whether it promotes hiPSCs differentiation and transplantation needs further study. Here, we overexpressed miR-210-5p in hiPSCs to study its roles and mechanisms. We found that miR-210-5p promoted the differentiation of hiPSCs into dopaminergic neural precursors and reduced the expression of SMAD4 and SUFU meanwhile. Luciferase assays showed that miR-210-5p binded to SMAD4 and SUFU, which are key molecules in the key signals (TGF-ß and SHH) of hiPSCs differentiation. Furthermore, in the effect evaluation of cell transplantation into parkinsonian rats, the degree of behavioral recovery and the growth of transplanted cells in the group overexpressed miR-210-5p were similar to those in the positive group with all small molecule inhibitors/activators. Therefore, we conclude that miR-210-5p promotes the differentiation of hiPSCs into dopaminergic neural precursors by targeting SMAD4 and SUFU. In the therapeutic evaluation of cell transplantation, miR-210-5p can replace the use of corresponding small molecule inhibitors/activators to reduce cell death. This study provides an experimental basis and a new target for the miRNA-modified differentiation of hiPSCs and cell transplantation in clinical treatment of PD in the future.

Neural stem cell transplantation improves learning and memory by protecting cholinergic neurons and restoring synaptic impairment in an amyloid precursor protein/presenilin 1 transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent age­related neurodegenerative disorder. It is featured by the progressive accumulation of ß­amyloid (Aß) plaques and neurofibrillary tangles. This can eventually lead to a decrease of cholinergic neurons in the basal forebrain. Stem cell transplantation is an effective treatment for neurodegenerative diseases. Previous studies have revealed that different types of stem or progenitor cells can mitigate cognition impairment in different Alzheimer's disease mouse models. However, understanding the underlying mechanisms of neural stem cell (NSC) therapies for AD requires further investigation. In the present study, the effects and the underlying mechanisms of the treatment of AD by NSCs are reported. The latter were labelled with the enhanced green fluorescent protein (EGFP) prior to implantation into the bilateral hippocampus of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mouse model of AD. It was observed that the number of basal forebrain cholinergic neurons was restored and the expression of choline acetyltransferase (ChAT) protein was increased. Moreover, the levels of synaptophysin (SYP), postsynaptic density protein 95 (PSD­95) and microtubule­associated protein (MAP­2) were significantly increased in the hippocampus of NSC­treated AD mice. Notably, spatial learning and memory were both improved after transplantation of NSCs. In conclusion, the present study revealed that NSC transplantation improved learning and memory functions in an AD mouse model. This treatment allowed repairing of basal forebrain cholinergic neurons and increased the expression of the cognition­related proteins SYP, PSD­95 and MAP­2 in the hippocampus.

JAK2/STAT3 signaling mediates IL-6-inhibited neurogenesis of neural stem cells through DNA demethylation/methylation.

Neuroinflammation, considered as a pathological hallmark of Alzheimer's disease (AD), has been demonstrated to affect hippocampal neurogenesis and cognitive function. Interleukin-6 (IL-6) is a proinflammatory cytokine known to modulate neurogenesis. However, the mechanisms are still largely unknown. Here, we reported that IL-6 suppressed neurogenesis via a JAK2/STAT3 signaling in neural stem cells (NSCs). Importantly, we found that NeuroD1 (Neurogenic differentiation 1) gene expression, which drives NSCs neurodifferentiation, was regulated by TET3 and DNMT1 in a JAK2/STAT3-dependent manner. We further found that JAK2/STAT3 inhibition enhanced demethylation of NeuroD1 regulatory elements in IL-6-treated cells, which is related to the significant upregulation of TET3 expression as well as the decreased expression of DNMT1. Furthermore, Inhibiting JAK2/STAT3 significantly rescued the memory deficits and hippocampal neurogenesis dysfunction in APP/PS1 mice. Our data suggest that JAK2/STAT3 signaling plays a vital role in suppressing neurogenesis of NSCs exposed to IL-6 at the epigenetic level, by regulating DNA methylation/demethylation.

Effect of leukocyte inhibitory factor on neuron differentiation from human induced pluripotent stem cell-derived neural precursor cells.

Direct derivation of human induced pluripotent stem cells into neural precursor cells and differentiation of these into neurons holds great promise in the cell therapy of neurodegenerative diseases. However, the availability and survival rate of neurons requires improvement. In the present study, it was found that the addition of 5 ng/ml leukocyte inhibitory factor (LIF) during the process of differentiation significantly improved the expression of neuron­specific class III ß­tubulin (TUJ1) and microtubule­associated protein 2 (MAP2), as detected by immunofluorescence and western blotting. In addition, LIF improved the cell viability, increased the expression of phosphorylated­protein kinase B (AKT), downregulated the expression of proinflammatory cytokines, including interleukin­1α (IL­1α) and tumor necrosis factor­α (TNF-α), and upregulated the expression of anti­inflammatory cytokines, including interleukin­10 (IL­10) and transforming growth factor­ß (TGF-ß). After adding the phosphatidylinositol 3-kinase (PI3K)/AKT signaling inhibitor LY294002 or wortmannin to the LIF differentiation group, LIF-induced changes in the protein expression of TUJ1 and MAP2 were reversed, but this effect could not be prevented by rapamycin, a mechanistic target of rapamycin signaling inhibitor. The expression of cytokines associated with inflammation and cell viability was reversed by LY294002 and wortmannin, but not by rapamycin. In conclusion, LIF could improve neuronal differentiation and survival through the activation of PI3K/AKT signaling and the anti­inflammatory effect. The anti­inflammatory effect may be mediated by the activation of PI3K/AKT.

NF-κB pathway link with ER stress-induced autophagy and apoptosis in cervical tumor cells.

Targeting endoplasmic reticulum (ER) stress is being investigated for its anticancer effect in various cancers, including cervical cancer. However, the molecular pathways whereby ER stress mediates cell death remain to be fully elucidated. In this study, we confirmed that ER stress triggered by compounds such as brefeldin A (BFA), tunicamycin (TM), and thapsigargin (TG) leads to the induction of the unfolded protein response (UPR) in cervical cancer cell lines, which is characterized by elevated levels of inositol-requiring kinase 1α, glucose-regulated protein-78, and C/EBP homologous protein, and swelling of the ER observed by transmission electron microscope (TEM). We found that BFA significantly increased autophagy in tumor cells and induced TC-1 tumor cell death in a dose-dependent manner. BFA increased punctate staining of LC3 and the number of autophagosomes observed by TEM in TC-1 and HeLa cells. The autophagic flux was also assessed. Bafilomycin, which blocked degradation of LC3 in lysosomes, caused both LC3I and LC3II accumulation. BFA initiated apoptosis of TC-1 tumor cells through activation of the caspase-12/caspase-3 pathway. At the same time, BFA enhanced the phosphorylation of IκBα protein and translocation into the nucleus of NF-κB p65. Quinazolinediamine, an NF-κB inhibitor, attenuated both autophagy and apoptosis induced by BFA; meanwhile, it partly enhances survival of cervical cancer cells following BFA treatment. In conclusion, our results indicate that the cross-talk between ER stress, autophagy, apoptosis, and the NF-κB pathways controls the fate of cervical cancer cells. Careful evaluation should be given to the addition of an NF-κB pathway inhibitor to treat cervical cancer in combination with drugs that induce ER stress-mediated cell death.

PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications.

Although valproic acid (VPA), has been shown to induce neuronal differentiation of neural stem cells (NSCs), the underlying mechanisms remain poorly understood. Here we investigated if and how mammalian target of rapamycin (mTOR) signaling is involved in the neuronal differentiation of VPA-induced NSCs. Our data demonstrated that mTOR activation not only promoted but also was necessary for the neuronal differentiation of NSCs induced by VPA. We further found that inhibition of mTOR signaling blocked demethylation of neuron-specific gene neurogenin 1 (Ngn1) regulatory element in induced cells. These are correlated with the significant alterations of passive DNA demethylation and the active DNA demethylation pathway in the Ngn1 promoter, but not the suppression of lysine-specific histone methylation and acetylation in the promoter region of Ngn1. These findings highlight a potentially important role for mTOR signaling, by working together with DNA demethylation, to influence the fate of NSCs via regulating the expression of Ngn1 in VPA-induced neuronal differentiation of NSCs.

Mitochondrial FOXO3a is involved in amyloid ß peptide-induced mitochondrial dysfunction.

Mitochondrial dysfunction is a hallmark of amyloid ß peptide (Aß)-induced neuronal toxicity in Alzheimer's disease (AD). However, the precise mechanism(s) of Aß-induced mitochondrial dysfunction has not been fully understood. There is evidence that Forkhead box O3a (FOXO3a) is normally present in neuronal mitochondria. Using HT22 murine hippocampal neuronal cells and primary hippocampal neurons, the present study investigated whether mitochondrial FOXO3a was involved in mitochondrial dysfunction induced by Aß. It was found that Aß induced dephosphorylation and mitochondrial translocation of FOXO3a. In addition, Aß enhanced association of FOXO3a with mitochondrial DNA (mtDNA), causing a decrease in the expression of cytochrome c oxidase subunit 1 (COX1) and the activity of COX. In addition, Aß-induced mitochondrial dysfunction, indicated by the decrease in 3- (4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) conversion, mitochondrial adenosine triphosphate (ATP) production and COX activity, could be suppressed by knockdown of FOXO3a (FOXO3a-KD). These results provide new insights into the mechanism underlying Aß-induced neurotoxicity and open up new therapeutic perspectives for AD.

Treatment Efficacy of NGF Nanoparticles Combining Neural Stem Cell Transplantation on Alzheimer's Disease Model Rats.

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia. It causes progressive brain disorder involving loss of normal memory and thinking skills. The transplantation of neural stem cells (NSCs) has been reported to improve learning and memory function of AD rats, and protects basal forebrain cholinergic neurons. Nerve growth factor - poly (ethylene glycol) - poly (lactic-co-glycolic acid)-nanoparticles (NGF-PEG-PLGA-NPs) can facilitate the differentiation of NSCs in vitro. This study thus investigated the treatment efficacy of NGF-PEG-PLGA-NPs combining NSC transplantation in AD model rats. MATERIAL AND METHODS: AD rats were prepared by injection of 192IgG-saporin into their lateral ventricles. Embryonic rat NSCs were separated, induced by NGF-PEG-PLGA-NPs in vitro, and were transplanted. The Morris water-maze test was used to evaluate learning and memory function, followed by immunohistochemical staining for basal forebrain cholinergic neurons, hippocampal synaptophysin, and acetylcholine esterase (AchE) fibers. RESULTS: Rats in the combined treatment group had significantly improved spatial learning ability compared to AD model animals (p<0.05). The number of basal forebrain cholinergic neurons, hippocampal synaptophysin, and AchE-positive fibers were all significantly larger than in the NSC-transplantation group, with no difference from control animals. CONCLUSIONS: NGF-PEG-PLGA-NPs plus NSC transplantation can significantly improve learning and memory functions of AD rats, replenish basal forebrain cholinergic neurons, and help form hippocampal synapses and AchE-positive fibers. These findings may offer practical support for and insight into treatment of Alzheimer's disease.

Incorporation of ß-sitosterol into the membrane prevents tumor necrosis factor-α-induced nuclear factor-κB activation and gonadotropin-releasing hormone decline.

It has been demonstrated that hypothalamus has a programmatic role in aging development, and this role of hypothalamus is mediated by nuclear factor-κB (NF-κB)-directed gonadotropin-releasing hormone (GnRH) decline. ß-Sitosterol (BS), one of the most common phytosterols in the diet, is able to inhibit pro-inflammatory NF-κB signaling. It has been demonstrated that dietary BS can enter the brain and accumulates in brain cell membranes. However, it is unknown whether and how membrane BS affects GnRH release. Using GT1-7 cells, a cell line of GnRH neurons, this study investigated if membrane BS had an influence on GnRH release. It was found that incorporation of BS into the membrane could prevent tumor necrosis factor-α (TNF-α)-induced GnRH decline. The underlying basis involves inhibition of NF-κß activation via estrogen receptor (ER)-mediated inhibition of inhibitor of nuclear factor κB (Iκß) processing. These results extend existing data regarding the beneficial effects of BS, and suggest the use of BS-enriched foods as anti-aging nutrients.

PPARα Agonist Fenofibrate Ameliorates Learning and Memory Deficits in Rats Following Global Cerebral Ischemia.

Increasing evidence demonstrates that local inflammation contributes to neuronal death following cerebral ischemia. Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to exhibit many pharmacological effects including anti-inflammatory functions. The aim of this study was to investigate the neuroprotective effects of PPARα agonist fenofibrate on the behavioral dysfunction induced by global cerebral ischemia/reperfusion (GCI/R) injury in rats. The present study showed that fenofibrate treatment significantly reduced hippocampal neuronal death, and improved memory impairment and hippocampal neurogenesis after GCI/R. Fenofibrate administration also inhibited GCI/R-induced over-activation of microglia but not astrocytes and prevented up-regulations of pro-inflammatory mediators in hippocampus. Further study demonstrated that treatment with fenofibrate suppressed GCI/R-induced activations of P65 NF-κB and P38 MAPK. Our data suggest that the PPARα agonist fenofibrate can exert functional recovery of memory deficits and neuroprotective effect against GCI/R in rats via triggering of neurogenesis and anti-inflammatory effect mediated by inhibiting activation of P65 NF-κB and P38 MAPK in the hippocampus, which can contribute to improvement in neurological deficits.

Valproic acid alleviates memory deficits and attenuates amyloid-ß deposition in transgenic mouse model of Alzheimer's disease.

In the brains of patients with Alzheimer's disease (AD) and transgenic AD mouse models, astrocytes and microglia activated by amyloid-ß (Aß) contribute to the inflammatory process that develops around injury in the brain. Valproic acid (VPA) has been shown to have anti-inflammatory function. The present study intended to explore the therapeutic effect of VPA on the neuropathology and memory deficits in APPswe/PS1ΔE9 (APP/PS1) transgenic mice. Here, we report that VPA-treated APP/PS1 mice markedly improved memory deficits and decreased Aß deposition compared with the vehicle-treated APP/PS1 mice. Moreover, the extensive astrogliosis and microgliosis as well as the increased expression in interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in the hippocampus and cortex of APP/PS1 transgenic mice were significantly reduced following administration of VPA, which attenuated neuronal degeneration. Concomitantly, VPA alleviated the levels of p65 NF-κB phosphorylation and enhanced the levels of acetyl-H3, Bcl-2, and phospho-glycogen synthase kinase (GSK)-3ß that occurred in the hippocampus of APP/PS1 transgenic mice. These results demonstrate that VPA could significantly ameliorate spatial memory impairment and Aß deposition at least in part via the inhibition of inflammation, suggesting that administration of VPA could provide a therapeutic approach for AD.

Estrogen receptor α promotes non-amyloidogenic processing of platelet amyloid precursor protein via the MAPK/ERK pathway.

Deposition of amyloid ß peptide (Aß), a proteolytic product of amyloid precursor protein (APP), in senile plaques and in the walls of cerebral blood vessels is a hallmark of Alzheimer's disease (AD). Platelets contain high levels of APP and Aß and may contribute to amyloid deposits seen in AD. However, the biochemical mechanism(s) involved in the regulation of platelet APP metabolism are largely unknown. The estrogen receptor α (ERα) is found to be expressed in platelets. It has not been elucidated whether ERα-mediated non-genomic signaling intervenes with platelet APP processing. Using ERα knock-out (α-ERKO) mice and wild type (WT) littermates, the present study demonstrated that ERα-specific agonist propylpyrazole triol (PPT) promoted non-amyloidogenic processing of platelet APP via the mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) pathway. The underlying basis involves direct association of activated ERK with a disintegrin and metalloprotease domain 17 (ADAM17, an α-secretase candidate) and ERK-dependent threonine phosphorylation of ADAM17. These results suggest that selective modulation of ERα in peripheral target tissues may serve as an anti-amyloidogenic strategy for AD and other amyloidogenic diseases.

Tanshinone IIA promotes non-amyloidogenic processing of amyloid precursor protein in platelets via estrogen receptor signaling to phosphatidylinositol 3-kinase/Akt.

Amyloid ß peptide (Aß) is a proteolytic product of amyloid precursor protein (APP). Recent findings suggested that platelet-derived Aß is closely associated with the pathogenesis of atherosclerosis (AS). Tanshinone IIA (Tan IIA), a pharmacologically active component of the Chinese herb Salvia miltiorrhiza Bunge, has long been used to treat AS and was also identified as a phytoestrogen. However, it has not been elucidated whether Tan IIA intervenes with platelet APP processing and whether such an intervention is associated with its estrogenic activity. Using human platelets, this study demonstrated that Tan IIA promoted the non-amyloidogenic cleavage of APP via estrogenic activity. The phosphatidylinositol 3-kinase/Akt pathway may be involved in this effect of Tan IIA on platelet APP metabolism as a downstream effector of estrogen receptor signaling. This study aimed to extend the existing data and provide new insights into the mechanism underlying the vasoprotective effect of Tan IIA.

Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in ß-amyloid rat model of Alzheimer's disease.

BACKGROUND: Endogenously produced hydrogen sulfide (H(2)S) may have multiple functions in brain. An increasing number of studies have demonstrated its anti-inflammatory effects. In the present study, we investigated the effect of sodium hydrosulfide (NaHS, a H(2)S donor) on cognitive impairment and neuroinflammatory changes induced by injections of Amyloid-ß(1-40) (Aß(1-40)), and explored possible mechanisms of action. METHODS: We injected Aß(1-40) into the hippocampus of rats to mimic rat model of Alzheimer's disease (AD). Morris water maze was used to detect the cognitive function. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was performed to detect neuronal apoptosis. Immunohistochemistry analyzed the response of glia. The expression of interleukin (IL)-1ß and tumor necrosis factor (TNF)-α was measured by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The expression of Aß(1-40), phospho-p38 mitogen-activated protein kinase (MAPK), phospho-p65 Nuclear factor (NF)-κB, and phospho-c-Jun N-terminal Kinase (JNK) was analyzed by western blot. RESULTS: We demonstrated that pretreatment with NaHS ameliorated learning and memory deficits in an Aß(1-40) rat model of AD. NaHS treatment suppressed Aß(1-40)-induced apoptosis in the CA1 subfield of the hippocampus. Moreover, the over-expression in IL-1ß and TNF-α as well as the extensive astrogliosis and microgliosis in the hippocampus induced by Aß(1-40) were significantly reduced following administration of NaHS. Concomitantly, treatment with NaHS alleviated the levels of p38 MAPK and p65 NF-κB phosphorylation but not JNK phosphorylation that occurred in the Aß(1-40)-injected hippocampus. CONCLUSIONS: These results indicate that NaHS could significantly ameliorate Aß(1-40)-induced spatial learning and memory impairment, apoptosis, and neuroinflammation at least in part via the inhibition of p38 MAPK and p65 NF-κB activity, suggesting that administration of NaHS could provide a therapeutic approach for AD.

WITHDRAWN: Transplantation of bone mesenchymal stem cells containing the nerve growth factor gene in adult rat brain with Fimbria Fornix lesion.

Bone marrow-derived mesenchymal stem cells (BMSCs) are a promising source for cell-based treatment of brain injury, but the therapy of BMSCs is restricted by low cell survival. We examined whether nerve growth factor (NGF) improve BMSCs viability in the brain with Fimbria-Fornix lesion (FF). After transduction of NGF gene via recombinant retroviral vectors, the rat BMSCs were transformed into the NGF-GFP positive BMSCs, nearly 100% of cells expressed NGF. After transplanted into basal forebrain of rat with FF, the NGF-GFP positive BMSCs expressed the exogenous NGF gene in the host brain, and interesting, the survival number of BMSCs in the NGF group was significant more than that of the void plasmid group. Furthermore, the number of choline acetyltransferase (ChAT) immunoreactive neurons of NGF group was also significant higher than those of the void plasmid group (p<0.05) or the PBS group (p<0.01). Performance in the water maze test was improved in these rats in NGF group. These results indicate that NGF increased BMSCs survival in brain with FF, which results in better improvement of brain function than injected with BMSCs alone.

Bone mesenchymal stem cells for gene transfer of NGF to the adult rat brain: rescue the NGFR p75 positive neurons from fimbria-fornix lesion-induced degeneration.

The study was to evaluate the therapeutic benefit of transplanted bone mesenchymal stem cells (BMSCs) transfected never growth factor (NGF) gene and GFP gene (as a reporter gene), in treating the rat with fimbria-fornix lesion. After transduction of NGF gene via recombinant retroviral vectors into the rat BMSCs, BMSCs were therefore transformed into the GFP-NGF positive BMSCs, nearly 100% of BMSCs expressed NGF, and then transplanted into basal forebrain of rat with fimbria-fornix lesion. After 2 weeks post-transplantation, the GFP-NGF positive BMSCs survive and fuse in vivo with astroglia or NGFR p75 positive neurons in the basal forebrain, no evidence of transdifferentiation was observed in this study. The number of NGFR p75 positive neurons in basal forebrain of NGF group was significantly higher than those of the void plasmid group (p < 0.05) or the PBS group (p < 0.01). These results indicate that the GFP-NGF positive BMSCs provide, by way of paracrine, NGF that effectively perform the functions of neuroprotection, which cell fusion may be also contribute to.

[Damaging nucleus centromedianus thalami for treatment of cancer pain in experimental and clinical aspects].

BACKGROUND & OBJECTIVE: There is no perfect method to control cancer pain. It is reported that nucleus centromedianus thalami plays a crucial role in the analgesia of central nerve system. The authors conducted this study, based on rat experiments, together with the clinical treatment of more than 90 cases involving various cancer pains, to explore the pain-relieving effects after damaging nucleus centromedianus thalami. METHODS: Ten SD rats, whose nucleus centromedianus thalami were damaged by electrolysis, were chosen, and then measured the pain degree by applying electricity to stimulate the tails of the rats. Meanwhile, another 10 rats, whose nucleus centromedianus thalami were not damaged, were chosen as the control group, among whom the same operation procedure as the above mentioned was carried out. The range of pain scale of the rats was measured by the alteration of the electric intensity. A total of 90 cases of intractable cancer pain were treated, including 36 cases of lung cancer, 21 cases of nasopharyngeal carcinoma, 10 cases of intestinal cancer, 8 cases of cancer of pancreas, 8 cases of osteocarcinoma, 4 cases of carcinoma of kidney, 3 cases of hepatocarcinoma. The brain stereotactic technique was used to damage the nucleus centromedianus thalami with radiofrequency coagulation lesions. The 10-grade method recommended by WHO was used to rank pain degree. RESULTS: Pain scale of rats in the first group rose from 0.152+/-0.034 mA prior to the damage to 0.326+/-0.05 afterwards, with a significant difference (P< 0.001), while the pain scale of the control group dropped from 0.142+/-0.027 mA prior to the operation to 0.138+/-0.035 mA afterwards, with no remarkable difference (P > 0.05). To patients with cancer pain, the average pain grade in this study went above 7 scores, but dropped to 0-3 scores after operation, according to the 10 grade method by WHO. A life-long tracing observation indicted that cancer pain in 24 cases relapsed to varying degrees but below 5 scores, the rest of the patients were analgesic persistently, 3 cases among whom lasted for as long as 2 years. The incidence cases of operational complications were 15 of somnolence, 10 of urinary incontinence, 8 of divagation, and 3 of unilateral oculomotor paralysis. These complications released after symptomatic treatments. CONCLUSION: Nucleus centromedianus thalami damage is an effective way to relieve cancer pain, as well as the complications should be paid attention.