Attenuating mitochondrial dysfunction and morphological disruption with PT320 delays dopamine degeneration in MitoPark mice.

BACKGROUND: Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood. METHODS: In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse. RESULTS: Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae. CONCLUSION: Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD.

MANF protein expression is upregulated in immune cells in the ischemic human brain and systemic recombinant MANF delivery in rat ischemic stroke model demonstrates anti-inflammatory effects.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) has cytoprotective effects on various injuries, including cerebral ischemia, and it can promote recovery even when delivered intracranially several days after ischemic stroke. In the uninjured rodent brain, MANF protein is expressed almost exclusively in neurons, but post-ischemic MANF expression has not been characterized. We aimed to investigate how endogenous cerebral MANF protein expression evolves in infarcted human brains and rodent ischemic stroke models. During infarct progression, the cerebral MANF expression pattern both in human and rat brains shifted drastically from neurons to expression in inflammatory cells. Intense MANF immunoreactivity took place in phagocytic microglia/macrophages in the ischemic territory, peaking at two weeks post-stroke in human and one-week post-stroke in rat ischemic cortex. Using double immunofluorescence and mice lacking MANF gene and protein from neuronal stem cells, neurons, astrocytes, and oligodendrocytes, we verified that MANF expression was induced in microglia/macrophage cells in the ischemic hemisphere. Embarking on the drastic expression transition towards inflammatory cells and the impact of blood-borne inflammation in stroke, we hypothesized that exogenously delivered MANF protein can modulate tissue recovery processes. In an attempt to enhance recovery, we designed a set of proof-of-concept studies using systemic delivery of recombinant MANF in a rat model of cortical ischemic stroke. Intranasal recombinant MANF treatment decreased infarct volume and reduced the severity of neurological deficits. Intravenous recombinant MANF treatment decreased the levels of pro-inflammatory cytokines and increased the levels of anti-inflammatory cytokine IL-10 in the infarcted cortex one-day post-stroke. In conclusion, MANF protein expression is induced in activated microglia/macrophage cells in infarcted human and rodent brains, and this could implicate MANF's involvement in the regulation of post-stroke inflammation in patients and experimental animals. Moreover, systemic delivery of recombinant MANF shows promising immunomodulatory effects and therapeutic potential in experimental ischemic stroke.

A Pineal Germinoma with Rapid Enlargement following Tumor Resection.

The natural course of pineal germ cell tumors (GCTs), particularly their post-operative progression, is not well understood. We report a rare case of pineal region GCT showing rapid enlargement within 2 weeks following surgical resection. A young adult male presented with progressive headache and diplopia for several weeks. Although elevation of ß-human chorionic gonadotropin (ß-HCG) and α-fetoprotein (AFP) levels suggested that a large pineal mass lesion observed on magnetic resonance imaging (MRI) might be a ß-HCG/AFP-producing tumor, whether the mass was truly a GCT remained unclear. We performed an endoscopy-assisted suboccipital infratentorial approach with removal of the tumor that was diagnosed as germinoma via histopathological investigation. During the week preceding chemotherapy, the patient's consciousness rapidly worsened. MRI showed that the residual pineal germinoma had enlarged and even compressed the tectum and thalamus. Emergency chemotherapy and radiotherapy were prescribed, and the patient received invasive ventilation for respiratory failure. Unexpectedly, the patient recovered within a short period. Importantly, total regression of the pineal germinoma, accompanied by ß-HCG and AFP levels returning to normal range, was observed 4 months after chemotherapy. These phenomena suggest that the rapid enlargement of the pineal germinoma, which might be induced by aggressive surgical cytoreduction, responds well to chemoradiotherapy.

Topping-off Surgery Versus Transforaminal Lumbar Intervertebral Fusion for Combined One-level Spondylolisthesis and Adjacent Lumbar Disc Herniation: A Comparative Study of Clinical Efficacy and Radiographic Outcomes With a Two-year Follow-up.

BACKGROUND/AIM: To investigate the radiographic and clinical outcomes in patients diagnosed with multilevel lumbar spine degeneration, undergoing hybrid stabilization with an interspinous device (IPD) adjacent to spine fusion, as compared with those experiencing three-segment or two-segment transforaminal lumbar interbody fusion (TLIF) via minimally invasive surgery (MIS). PATIENTS AND METHODS: Between 2015-2017, 51 consecutive patients who received three-segment TLIF, interspinous dynamic stabilization combined with two-segment TLIF (topping-off surgery), and two-segment TLIF coupled with adjacent level lumbar discectomy (two-segment TLIF+discectomy) were studied. These three operative procedures were performed by one neurosurgeon at the same hospital. Post-operative analysis of the two-year analysis was conducted by another neurosurgeon. Radiographic and clinical outcomes were compared among the three groups. RESULTS: Duration of surgery was significantly shorter in the topping-off surgery and TLIF+discectomy compared to three-segment TLIF group. Although there was no difference in hospital stay among the three groups, visual analogue scale (VAS) and Oswestry disability index (ODI) were less in the topping-off group than in the three-segment TLIF or two-segment TLIF+discectomy groups after one week and three months follow-up, respectively. Disc high index (DHI) in adjacent segment decreased from before the operation to two years follow-up postoperatively in the two-segment TLIF+discectomy group. In contrast, DHI in the segment adjacent to spondylolisthesis increased from before the operation to last follow-up post-operatively in the three-segment TLIF group. Compared with the two-segment TLIF+discectomy group, the topping-off group showed higher foramen high index at the IPD level. While there was no difference in segment range of motion among the three groups, the topping-off group showed preserved total range of motion at a two-year follow-up, as compared with the three-segment TLIF group. CONCLUSION: Under strict indications, topping-off surgery is an acceptable alternative to fusion surgery for spondylolisthesis combined with adjacent disc degeneration.

PT320, a Sustained-Release GLP-1 Receptor Agonist, Ameliorates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease.

To determine the efficacy of PT320 on L-DOPA-induced dyskinetic behaviors, and neurochemistry in a progressive Parkinson's disease (PD) MitoPark mouse model. To investigate the effects of PT320 on the manifestation of dyskinesia in L-DOPA-primed mice, a clinically translatable biweekly PT320 dose was administered starting at either 5 or 17-weeks-old mice. The early treatment group was given L-DOPA starting at 20 weeks of age and longitudinally evaluated up to 22 weeks. The late treatment group was given L-DOPA starting at 28 weeks of age and longitudinally observed up to 29 weeks. To explore dopaminergic transmission, fast scan cyclic voltammetry (FSCV) was utilized to measure presynaptic dopamine (DA) dynamics in striatal slices following drug treatments. Early administration of PT320 significantly mitigated the severity L-DOPA-induced abnormal involuntary movements; PT320 particularly improved excessive numbers of standing as well as abnormal paw movements, while it did not affect L-DOPA-induced locomotor hyperactivity. In contrast, late administration of PT320 did not attenuate any L-DOPA-induced dyskinesia measurements. Moreover, early treatment with PT320 was shown to not only increase tonic and phasic release of DA in striatal slices in L-DOPA-naïve MitoPark mice, but also in L-DOPA-primed animals. Early treatment with PT320 ameliorated L-DOPA-induced dyskinesia in MitoPark mice, which may be related to the progressive level of DA denervation in PD.

Endoscopically assisted presigmoid retrolabyrinthine approach to the lateral mesencephalic sulcus: a cadaveric study with comparison to the variant supracerebellar infratentorial approaches.

The supracerebellar infratentorial (SCIT) approach is commonly used to gain access to the lateral mesencephalic sulcus (LMS), which has been established as a safe entry point into the posterolateral midbrain. This study describes a lateral variant of the SCIT approach, the supreme-lateral SCIT approach, for accessing the LMS through the presigmoid retrolabyrinthine craniectomy and quantitatively compares this approach with the paramedian and extreme-lateral SCIT approaches. Anatomical dissections were performed in four cadaveric heads. In each head, the supreme-lateral SCIT approach was established on one side, following a detailed description of each step, whereas the paramedian and supreme-lateral SCIT approaches were established on the other side. Quantitative measurements of the exposed posterolateral midbrain, the angles of LMS entry, and the depth of surgical corridors were recorded and compared between the three SCIT approach variants. The supreme-lateral (67.70 ± 23.14 mm2) and extreme-lateral (70.83 ± 24.99 mm2) SCIT approaches resulted in larger areas of exposure anterior to the LMS than the paramedian SCIT approach (38.61 ± 9.84 mm2); the supreme-lateral SCIT approach resulted in a significantly smaller area of exposure posterior to the LMS (65.24 ± 6.81 mm2) than the other two variants (paramedian = 162.75 ± 31.98 mm2; extreme-lateral = 143.10 ± 23.26 mm2; both P < .001). Moreover, the supreme-lateral SCIT approach resulted in a surgical corridor with a shallower depth and a smaller angle relative to the horizontal plane than the other two variants. The supreme-lateral SCIT approach is a more lateral approach than the extreme-lateral SCIT approach, providing a subtemporal approach with direct LMS visualization. The supreme-lateral SCIT offers the benefits of both subtemporal and SCIT approaches and represents a suitable option for the management of selected midbrain pathologies.

Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage.

During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH. Here, we show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain's myeloid cells for the treatment of ICH.

Risk factors of postoperative hydrocephalus following decompressive craniectomy for spontaneous intracranial hemorrhages and intraventricular hemorrhage.

INTRODUCTION: Hydrocephalus is a complication of spontaneous intracerebral hemorrhage; however, its predictive relationship with hydrocephalus in this patient cohort is not understood. Here, we evaluated the incidence and risk factors of hydrocephalus after craniectomy. METHODS: Retrospectively studied data from 39 patients in the same hospital from 2016/01 to 2020/12 and analyzed risk factors for hydrocephalus. The clinical data recorded included patient age, sex, timing of surgery, initial Glasgow Coma Scale score, intracerebral hemorrhage (ICH) score, alcohol consumption, cigarette smoking, medical comorbidity, and blood data. Predictors of patient outcomes were determined using Student t test, chi-square test, and logistic regression. RESULTS: We recruited 39 patients with cerebral herniation who underwent craniectomy for spontaneous supratentorial hemorrhage. Persistent hydrocephalus was observed in 17 patients. The development of hydrocephalus was significantly associated with the timing of operation, cigarette smoking, and alcohol consumption according to the Student t test and chi-square test. Univariate and multivariate analyses suggested that postoperative hydrocephalus was significantly associated with the timing of surgery (P = .031) and cigarette smoking (P = .041). DISCUSSION: The incidence of hydrocephalus in patients who underwent delayed operation (more than 4 hours) was lower than that in patients who underwent an operation after less than 4 hours. nonsmoking groups also have lower incidence of hydrocephalus. Among patients who suffered from spontaneous supratentorial hemorrhage and need to receive emergent craniectomy, physicians should be reminded that postoperative hydrocephalus followed by ventriculoperitoneal shunting may be necessary in the future.

UPR Responsive Genes Manf and Xbp1 in Stroke.

Stroke is a devastating medical condition with no treatment to hasten recovery. Its abrupt nature results in cataclysmic changes in the affected tissues. Resident cells fail to cope with the cellular stress resulting in massive cell death, which cannot be endogenously repaired. A potential strategy to improve stroke outcomes is to boost endogenous pro-survival pathways. The unfolded protein response (UPR), an evolutionarily conserved stress response, provides a promising opportunity to ameliorate the survival of stressed cells. Recent studies from us and others have pointed toward mesencephalic astrocyte-derived neurotrophic factor (MANF) being a UPR responsive gene with an active role in maintaining proteostasis. Its pro-survival effects have been demonstrated in several disease models such as diabetes, neurodegeneration, and stroke. MANF has an ER-signal peptide and an ER-retention signal; it is secreted by ER calcium depletion and exits cells upon cell death. Although its functions remain elusive, conducted experiments suggest that the endogenous MANF in the ER lumen and exogenously administered MANF protein have different mechanisms of action. Here, we will revisit recent and older bodies of literature aiming to delineate the expression profile of MANF. We will focus on its neuroprotective roles in regulating neurogenesis and inflammation upon post-stroke administration. At the same time, we will investigate commonalities and differences with another UPR responsive gene, X-box binding protein 1 (XBP1), which has recently been associated with MANF's function. This will be the first systematic comparison of these two UPR responsive genes aiming at revealing previously uncovered associations between them. Overall, understanding the mode of action of these UPR responsive genes could provide novel approaches to promote cell survival.

Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential is allogenic immune reaction of tissue grafts by recipients. Cerebral dopamine neurotrophic factor (CDNF) was shown to possess immune-modulatory properties that benefit neurodegenerative diseases. We hypothesized that co-administration of CDNF with fetal ventral mesencephalic (VM) tissue can improve the success of VM replacement therapies by attenuating immune responses. Hemiparkinsonian rats were generated by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats, with/without CDNF administration. Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small-animal positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. In addition, transplantation-related inflammatory response was determined by uptake of [18F] FEPPA in the grafted side of striatum. Immunohistochemistry (IHC) examination was used to determine the survival of the grated dopaminergic neurons in the striatum and to investigate immune-modulatory effects of CDNF. The modulation of inflammatory responses caused by CDNF might involve enhancing M2 subset polarization and increasing fractal dimensions of 6-OHDA-treated BV2 microglial cell line. Analysis of CDNF-induced changes to gene expressions of 6-OHDA-stimulated BV2 cells implies that these alternations of the biomarkers and microglial morphology are implicated in the upregulation of protein kinase B signaling as well as regulation of catalytic, transferase, and protein serine/threonine kinase activity. The effects of CDNF on 6-OHDA-induced alternation of the canonical pathway in BV2 microglial cells is highly associated with PI3K-mediated phagosome formation. Our results are the first to show that CDNF administration enhances the survival of the grafted dopaminergic neurons and improves functional recovery in PD animal model. Modulation of the polarization, morphological characteristics, and transcriptional profiles of 6-OHDA-stimualted microglia by CDNF may possess these properties in transplantation-based regenerative therapies.

Tetrabenazine Mitigates Aberrant Release and Clearance of Dopamine in the Nigrostriatal System, and Alleviates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease.

BACKGROUND: L-DOPA-induced dyskinesia (LID), occurring with aberrant processing of exogenous L-DOPA in the dopamine-denervated striatum, is a main complication of levodopa treatment in Parkinson's disease. OBJECTIVE: To characterize the effects of the vesicular antagonist tetrabenazine (TBZ) on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson's disease. METHODS: 20-week-old MitoPark mice were co-treated or separately administered TBZ and L-DOPA for 14 days. Abnormal involuntary movements (AIMs) and locomotor activity were analyzed. To explore dopamine (DA) transmission, fast scan cyclic voltammetry was used to assess presynaptic DA dynamics in striatal slices following treatments. PET imaging with 4-[18F]-PE2I, ADAM and immunoblotting assays were used to detect receptor protein changes in the DA-denervated striatum. Finally, nigrostriatal tissues were collected for HPLC measures of DA, serotonin and their metabolites. RESULTS: A single injection of TBZ given in the interval between the two L-DOPA/Carbidopa treatments significantly attenuated L-DOPA-induced AIMs expression and locomotor hyperactivity. TBZ was shown to reduce tonic and phasic release of DA following L-DOPA treatment in DA-denervated striatal tissue. In the DA-depleted striatum, TBZ decreased the expression of L-DOPA-enhanced D1 receptors and the serotonin reuptake transporter. Neurochemical analysis indicated that TBZ attenuated L-DOPA-induced surges of DA levels by promoting DA turnover in the nigrostriatal system. CONCLUSIONS: Our findings demonstrate that TBZ diminishes abnormal striatal DA transmission, which involves the ability of TBZ to modulate the presymptomatic dynamics of DA, and then mitigate aberrant release of exogenous L-DOPA from nerve terminals. The results support the potential of repositioning TBZ to counteract LID development.

Post-stroke Delivery of Valproic Acid Promotes Functional Recovery and Differentially Modifies Responses of Peri-Infarct Microglia.

The specific role of peri-infarct microglia and the timing of its morphological changes following ischemic stroke are not well understood. Valproic acid (VPA) can protect against ischemic damage and promote recovery. In this study, we first determined whether a single dose of VPA after stroke could decrease infarction area or improve functional recovery. Next, we investigated the number and morphological characteristic of peri-infarct microglia at different time points and elucidated the mechanism of microglial response by VPA treatment. Male Sprague-Dawley rats were subjected to distal middle cerebral artery occlusion (dMCAo) for 90 min, followed by reperfusion. Some received a single injection of VPA (200 mg/kg) 90 min after the induction of ischemia, while vehicle-treated animals underwent the same procedure with physiological saline. Infarction volume was calculated at 48 h after reperfusion, and neurological symptoms were evaluated. VPA didn't significantly reduce infarct volume but did ameliorate neurological deficit at least partially compared with vehicle. Meanwhile, VPA reduced dMCAo-induced elevation of IL-6 at 24 h post-stroke and significantly decreased the number of CD11b-positive microglia within peri-infarct cortex at 7 days. Morphological analysis revealed that VPA therapy leads to higher fractal dimensions, smaller soma size and lower circularity index of CD11b-positive cells within peri-infarct cortex at both 2 and 7 days, suggesting that VPA has core effects on microglial morphology. The modulation of microglia morphology caused by VPA might involve HDAC inhibition-mediated suppression of galectin-3 production. Furthermore, qPCR analysis of CD11b-positive cells at 3 days post-stroke suggested that VPA could partially enhance M2 subset polarization of microglia in peri-infarct cortex. Analysis of VPA-induced changes to gene expressions at 3 days post-stroke implies that these alternations of the biomarkers and microglial responses are implicated in the upregulation of wound healing, collagen trimmer, and extracellular matrix genes within peri-infarct cortex. Our results are the first to show that a low dose of VPA promotes short-term functional recovery but does not alter infarct volume. The decreases in the expression of both IL-6 and galectin-3 might influence the morphological characteristics and transcriptional profiles of microglia and extracellular matrix remodeling, which could contribute to the improved recovery.

Endoscopic transcanal transpetrosal approach to the petroclival region: a cadaveric study with comparison to the Kawase approach.

This study introduces expanded application of the endoscopic transcanal approach with anterior petrosectomy (ETAP) in reaching the petroclival region, which was compared through a quantitative analysis to the middle fossa transpetrosal-transtentorial approach (Kawase approach). Anatomical dissections were performed in five cadaveric heads. For each head, the ETAP was performed on one side with a detailed description of each step, while the Kawase approach was performed on the contralateral side. Quantitative measurements of the exposed area over the ventrolateral surface of the brainstem, and of the angles of attack to the posterior margin of the trigeminal nerve root entry zone (CN V-REZ) and porus acusticus internus (PAI) were obtained for statistical comparison. The ETAP provided significantly larger exposure over the ventrolateral surface of the pons (93.03 ± 21.87 mm2) than did the Kawase approach (34.57 ± 11.78 mm2). In contrast to the ETAP, the Kawase approach afforded greater angles of attack to the CN V-REZ and PAI in the vertical and horizontal planes. The ETAP is a feasible and minimally invasive procedure for accessing the petroclival region. In comparison to the Kawase approach, the ETAP allows for fully anterior petrosectomy and larger exposure over the ventrolateral surface of the brainstem without passing through the cranial nerves or requiring traction of the temporal lobe.

MANF Promotes Differentiation and Migration of Neural Progenitor Cells with Potential Neural Regenerative Effects in Stroke.

Cerebral ischemia activates endogenous reparative processes, such as increased proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) and migration of neural progenitor cells (NPCs) toward the ischemic area. However, this reparative process is limited because most of the NPCs die shortly after injury or are unable to arrive at the infarct boundary. In this study, we demonstrate for the first time that endogenous mesencephalic astrocyte-derived neurotrophic factor (MANF) protects NSCs against oxygen-glucose-deprivation-induced injury and has a crucial role in regulating NPC migration. In NSC cultures, MANF protein administration did not affect growth of cells but triggered neuronal and glial differentiation, followed by activation of STAT3. In SVZ explants, MANF overexpression facilitated cell migration and activated the STAT3 and ERK1/2 pathway. Using a rat model of cortical stroke, intracerebroventricular injections of MANF did not affect cell proliferation in the SVZ, but promoted migration of doublecortin (DCX)+ cells toward the corpus callosum and infarct boundary on day 14 post-stroke. Long-term infusion of MANF into the peri-infarct zone increased the recruitment of DCX+ cells in the infarct area. In conclusion, our data demonstrate a neuroregenerative activity of MANF that facilitates differentiation and migration of NPCs, thereby increasing recruitment of neuroblasts in stroke cortex.

MANF Is Essential for Neurite Extension and Neuronal Migration in the Developing Cortex.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) resident protein with neuroprotective effects. Previous studies have shown that MANF expression is altered in the developing rodent cortex in a spatiotemporal manner. However, the role of MANF in mammalian neurogenesis is not known. The aim of this study was to determine the role of MANF in neural stem cell (NSC) proliferation, differentiation, and cerebral cortex development. We found that MANF is highly expressed in neural lineage cells, including NSCs in the developing brain. We discovered that MANF-deficient NSCs in culture are viable and show no defect in proliferation. However, MANF-deficient cells have deficits in neurite extension upon neuronal differentiation. In vivo, MANF removal leads to slower neuronal migration and impaired neurite outgrowth. In vitro, mechanistic studies indicate that impaired neurite growth is preceded by reduced de novo protein synthesis and constitutively activated unfolded protein response (UPR) pathways. This study is the first to demonstrate that MANF is a novel and critical regulator of neurite growth and neuronal migration in mammalian cortical development.

Local administration of AAV-BDNF to subventricular zone induces functional recovery in stroke rats.

Migration of new neuroprogenitor cells (NPCs) from the subventricular zone (SVZ) plays an important role in neurorepair after injury. Previous studies have shown that brain derived neurotrophic factor (BDNF) enhances the migration of NPCs from SVZ explants in neonatal mice in vitro. The purpose of this study was to identify the role of BDNF in SVZ cells using AAV-BDNF in an animal model of stroke. BDNF protein production after AAV-BDNF infection was verified in primary neuronal culture. AAV-BDNF or AAV-RFP was injected into the left SVZ region of adult rats at 14 days prior to right middle cerebral artery occlusion (MCAo). SVZ tissues were collected from the brain and placed in Metrigel cultures 1 day after MCAo. Treatment with AAV-BDNF significantly increased the migration of SVZ cells in the stroke brain in vitro. In another set of animals, AAV-GFP was co-injected with AAV-BDNF or AAV-RFP to label cells in left SVZ prior to right MCAo. Local administration of AAV-BDNF significantly enhanced recovery of locomotor function and migration of GFP-positive cells from the SVZ toward the lesioned hemisphere in stroke rats. Our data suggest that focal administration of AAV-BDNF to the SVZ increases behavioral recovery post stroke, possibly through the enhancement of migration of cells from SVZ in stroke animals. Regional manipulation of BDNF expression through AAV may be a novel approach for neurorepair in stroke brains.

Endoscopic supracerebellar infratentorial retropineal approach for tumor resection.

BACKGROUND: Lesions located in the pineal region represent a surgical challenge. Multiple approaches to this region have been described, each with its advantages and disadvantages. We report the first application of the endoscopic supracerebellar infratentorial approach for complete resection of a pineal tumor. Unlike transventricular endoscopy, this technique poses no risk to the fornices and can be applied independent of ventricular size. CASE DESCRIPTION: A 21-year-old man sought treatment for diplopia. Magnetic resonance images of brain revealed a heterogeneous, contrast-enhancing mass that originated from the pineal gland. This tumor exerted the mass effect on the tectum and invaded to the bilateral dorso-medial thalamus and hypothalamus but caused no obstructive hydrocephalus. The results of a cytological study of the cerebrospinal fluid, alpha-fetoprotein, and beta-human chorionic gonadotropin were negative. The patient was referred for the surgical work-up. TECHNIQUE: The patient was positioned in the semi-sitting position. The supracerebellar infratentoria corridor was accessed through two paramedian burr holes, which provided natural by-gravity cerebellar traction. The excellent illumination and magnification without sacrificing the inferior occipital sinus could be achieved with the aid of the endoscope. The pineal tumor was resected completely via the full-endoscopic approach. Postoperatively, the patient's diplopia resolved completely, and his hospital course was uneventful. CONCLUSIONS: Taking the advantages of the endoscope and peculiar supracerebellar infratentoria corridor, we could successfully remove the gross-total tumor without violating the critical neurovascular structures. Moreover, this approach can be performed regardless of the size of the ventricle. Consequently, it is an excellent minimally invasive surgical option for resection of symptomatic pineal tumor.

CyberKnife stereotactic radiosurgical rhizotomy for refractory trigeminal neuralgia.

Stereotactic radiosurgery (SRS) has been established as an option for the treatment of trigeminal neuralgia (TN). Here, we report our experience of CyberKnife®-based (Accuray, Sunnyvale, CA, USA) stereotactic rhizotomy on medically refractory patients to determine its clinical effectiveness. Between January 2007 and December 2009, 14 selected patients underwent SRS for TN at our CyberKnife Center. Patients were evaluated for pain relief using a visual analog scale (VAS) score, time to reach pain relief (latency), duration of pain control, decrease of pain medication, occurrence of new dysesthesia, and side effects at the 3-month, 6-month, 1-year and 2-year follow-up. A literature analysis revealed that compared with other SRS systems, which can provide a high rate of pain control, CyberKnife® stereotactic rhizotomy yielded an earlier onset of pain relief in our cohort.

Use of spinous processes to determine the laterally angulated trajectory for placement of lateral mass screws: an image analysis.

BACKGROUND: Lateral mass screw placement techniques have been broadly described in the literature. Differences in these techniques are related to entry points, lateral angulations and the cephalocaudal axis. AIM: We evaluated 20 patients who underwent lateral mass screw placement between 2007 and 2009. Computed tomography (CT) scans of the cervical vertebrae were analyzed for each patient. MATERIAL AND METHODS: We measured the maximal transition from the midpoint of the lateral mass to a proposed intersection point by a line connecting the corresponding spinous process and outermost rim of the transverse foramen at each level. This determined an optimal entry point during the tip of screw tilted on the same level of spinous process. RESULTS: The results revealed that a screw entry point less than 3 mm medial to the midpoint of the lateral mass could safely avoid violation of the vertebral artery. CONCLUSIONS: The current study uses imaging analysis to demonstrate that spinous processes are an intraoperative landmark to aid surgeons in determining safe lateral mass screw trajectories. The limited-scale case results support our prediction from the image analysis. Depending on intraoperative landmarks, lateral mass screws could be safely and comfortably placed with good clinical outcomes.