An optimized intracerebroventricular injection of CD4+ T cells into mice.

The blood-brain barrier acts as a major barrier for the entrance of most therapeutics into the brain, impeding treatment for neurological disorders. Intracerebroventricular (ICV) injection of T cells is a useful tool for cell therapy of neurological disorders including neurodegenerative and neuropsychiatric diseases and brain tumors. Here, we present an optimized ICV injection of T cells with improved injection efficiency at pathological sites within the brain parenchyma. We describe details of the surgical procedure and verification of injection via immunohistochemistry. For complete details on the use and execution of this protocol, please refer to Fisher et al. (2014); Strominger et al., (2018); Mittal et al. (2019); Eremenko et al. (2019).

Intracerebroventricular streptozotocin induces behavioral impairments and increases short­term C3 gene expression in the hippocampus of Wistar rats.

A non­transgenic rat model based on intracerebroventricular injection of streptozotocin (STZ) has been used as an animal model to investigate mechanisms associated to the late onset of sporadic Alzheimer's disease, such as anatomical and behavioral impairments. However, molecular aspects related to gene expression, mainly in the hippocampus, require more investigation. Thus, this study evaluated the early and late cognitive functions and hippocampal gene expression after STZ administration. Male Wistar rats were divided into 4 groups: STZ (injected bilaterally), control group for the early memory function evaluation (1 month after surgery = phase 1, same volume of vehicle), and the same treatment for the late memory function evaluation (4 months after surgery = phase 2). The animals were observed in the elevated plus maze to assess behaviors related to anxiety, risk­assessment and fear­related memories. The behavioral tests were followed by brain removal and hippocampal dissection for RNA extraction and qRT­PCR to assess the expression levels of 4 Alzheimer's disease related genes: Mapt, Apoe, C3 and Ps­1. Animals from both phases showed increased time percentage and number of entries into the open arms, indicating risk behavior associated with anxiety, and an increased time percentage in the center square for both exposures (re­test) when compared to the control group, suggesting working memory impairment related to an aversive event. Statistical analyses indicated that the STZ group presented alterations in anxiety, memory and risk assessment responses. Additionally, one month after STZ administration, C3 gene assays revealed an increased expression. Therefore, current data indicate that neuroinflammatory events linked to the expression of pro inflammatory cytokines such as C3 are related to memory, anxiety and decision-making alterations.

Modified Frameless Stereotactic System for Intracerebral Delivery of Viral Vector in Young Children.

BACKGROUND: Stereotaxic surgery for viral vector delivery in young children is highly challenging because of their small cranial size, thin and fragile skull, and deformity of the skull or brain after prolonged bed ridden condition. OBJECTIVE: To develop a modified frameless stereotactic system especially suitable for intracerebral delivery of viral vector in young children for accurate localization of intracerebral targets during stereotactic surgery. METHODS: A modified frameless stereotactic system was developed for intracerebral delivery of viral vector in pediatric patients with congenital enzyme deficiency. Localization markers and a stereotactic stabilizer were designed specifically for surgery in pediatric patients, and this equipment is used along with a pre-existing frameless stereotactic and computer-assisted planning and navigation system. RESULTS: We applied this modified frameless stereotactic system to treat 10 children with aromatic L-amino acid decarboxylase deficiency. CONCLUSION: It is potentially suitable for stereotactic functional neurosurgery in pediatric patients as young as 1 yr and 8 mo of age.

Neuro-Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice.

AIMS: Mutations in DNA/RNA-binding factor (fused-in-sarcoma) FUS and superoxide dismutase-1 (SOD-1) cause amyotrophic lateral sclerosis (ALS). They were reproduced in SOD-1-G93A (SOD-1) and new FUS[1-359]-transgenic (FUS-tg) mice, where inflammation contributes to disease progression. The effects of standard disease therapy and anti-inflammatory treatments were investigated using these mutants. METHODS: FUS-tg mice or controls received either vehicle, or standard ALS treatment riluzole (8 mg/kg/day), or anti-inflammatory drug a selective blocker of cyclooxygenase-2 celecoxib (30 mg/kg/day) for six weeks, or a single intracerebroventricular (i.c.v.) infusion of Neuro-Cells (a preparation of 1.39 × 106 mesenchymal and hemopoietic human stem cells, containing 5 × 105 of CD34+ cells), which showed anti-inflammatory properties. SOD-1 mice received i.c.v.-administration of Neuro-Cells or vehicle. RESULTS: All FUS-tg-treated animals displayed less marked reductions in weight gain, food/water intake, and motor deficits than FUS-tg-vehicle-treated mice. Neuro-Cell-treated mutants had reduced muscle atrophy and lumbar motor neuron degeneration. This group but not celecoxib-FUS-tg-treated mice had ameliorated motor performance and lumbar expression of microglial activation marker, ionized calcium-binding adapter molecule-1 (Iba-1), and glycogen-synthase-kinase-3ß (GSK-3ß). The Neuro-Cells-treated-SOD-1 mice showed better motor functions than vehicle-treated-SOD-1 group. CONCLUSION: The neuropathology in FUS-tg mice is sensitive to standard ALS treatments and Neuro-Cells infusion. The latter improves motor outcomes in two ALS models possibly by suppressing microglial activation.

Use of ventriculostomy in the treatment of septic cavernous sinus thrombosis (SCST).

We present a novel treatment with the use of intraventricular antibiotics delivered through a ventriculostomy in a patient who developed septic cavernous sinus thrombosis after sinus surgery. A 65-year-old woman presented with acute on chronic sinusitis. The patient underwent a diagnostic left maxillary antrostomy, ethmoidectomy, sphenoidotomy and sinusotomy. Postoperatively, the patient experienced altered mental status with episodic fever despite treatment with broad-spectrum antimicrobial therapy. MRI of the brain showed extensive meningeal enhancement with the involvement of the right trigeminal and abducens nerve along with thick enhancement along the right pons and midbrain. MR arteriogram revealed a large filling defect within the cavernous sinus. Intraventricular gentamicin was administered via external ventricular drain (ie, ventriculostomy) every 24 hours for 14 days with continued treatment of intravenous ceftriaxone and metronidazole. The patient improved with complete resolution of her cavernous sinus meningitis on repeat brain imaging at 6 months posthospitalisation.

Continuous and bolus intraventricular topotecan prolong survival in a mouse model of leptomeningeal medulloblastoma.

Leptomeningeal metastasis remains a difficult clinical challenge. Some success has been achieved by direct administration of therapeutics into the cerebrospinal fluid (CSF) circumventing limitations imposed by the blood brain barrier. Here we investigated continuous infusion versus bolus injection of therapy into the CSF in a preclinical model of human Group 3 medulloblastoma, the molecular subgroup with the highest incidence of leptomeningeal disease. Initial tests of selected Group 3 human medulloblastoma cell lines in culture showed that D283 Med and D425 Med were resistant to cytosine arabinoside and methotrexate. D283 Med cells were also resistant to topotecan, whereas 1 µM topotecan killed over 99% of D425 Med cells. We therefore introduced D425 Med cells, modified to express firefly luciferase, into the CSF of immunodeficient mice. Mice were then treated with topotecan or saline in five groups: continuous intraventricular (IVT) topotecan via osmotic pump (5.28 µg/day), daily bolus IVT topotecan injections with a similar daily dose (6 µg/day), systemic intraperitoneal injections of a higher daily dose of topotecan (15 µg/day), daily IVT pumped saline and daily intraperitoneal injections of saline. Bioluminescence analyses revealed that both IVT topotecan treatments effectively slowed leptomeningeal tumor growth in the brains. Histological analysis showed that they were associated with localized brain necrosis, possibly due to backtracking of topotecan around the catheter. In the spines, bolus IVT topotecan showed a trend towards slower tumor growth compared to continuous (pump) IVT topotecan, as measured by bioluminescence. Both continuous and bolus topotecan IVT showed longer survival compared to other groups. Thus, both direct IVT topotecan CSF delivery methods produced better anti-medulloblastoma effect compared to systemic therapy at the dosages used here.

Protective effect of betulinic acid against intracerebroventricular streptozotocin induced cognitive impairment and neuronal damage in rats: Possible neurotransmitters and neuroinflammatory mechanism.

BACKGROUND: The purpose of the study was to explore the therapeutic potential of Betulinic acid (BA) in streptozotocin (STZ) induced memory damage in experimental rats. METHODS: STZ (3mg/kg bilaterally) as intracerebroventrical (icv) route was administered on day 1 and 3 in rats. Donepezil (5mg/kg/day po), used as standard, and BA (5, 10 and 15mg/kg/day po) were administered after 1h of 1st STZ infusion up to 21days. Object recognition task (ORT) for non-spatial, Morris water maze (MWM) for spatial and locomotor activity were performed to evaluate behavioral changes in rats. On 22nd day, animals were decapitated and hippocampus was separated to perform biochemical (AChE, LPO, GSH, nitrite), neuroinflammatory (TNF-α, IL-1ß, and IL-6), neurotransmitters (NTs) (dopamine, norepinephrine and serotonin) analysis. RESULTS: STZ infusion significantly impaired memory as observed in MWM and ORT, increased oxidative stress, pro-inflammatory cytokine's level and altered NTs level. Moreover, BA demonstrated a neuroprotective effect in a dose-dependent manner. BA dose dependently (5, 10 and 15mg/kg) significantly restore STZ induced memory changes and pathological abnormalities in rat brain. CONCLUSIONS: The findings of the current study suggests that BA protect rat brain from STZ induced neuronal damage via acting through multiple mechanisms and would be used to curb cognitive decline associated with neurodegenerative disorders especially AD.

Lowering the concentration affects the migration and viability of intracerebroventricular-delivered human mesenchymal stem cells.

Due to their widely known therapeutic benefits, mesenchymal stem cells have been proposed as a novel treatment option for a wide range of diseases including Alzheimer's disease. To maximize these benefits, critical factors such as delivery route, cell viability, and cell migration must be accounted for. Out of the various delivery routes to the brain, the intracerebroventricular (ICV) route stands out due to the widespread distribution that can occur via cerebrospinal fluid flow. The major objective of this present study was to observe how altering cell concentration influences the migration and viability of human umbilical cord blood derived-mesenchymal stem cells (hUCB-MSCs), delivered via ICV injection, in the brains of wild-type (WT) mice. C3H/C57 WT mice were divided into three groups and were injected with 1 × 105 hUCB-MSCs suspended in varying volumes: high (3 µl), middle (5 µl), and low (7 µl) concentrations, respectively. Lowering the concentration increased the migratory capabilities and elevated the viability of hUCB-MSCs. These results suggest that cell concentration can affect the physiological state of hUCB-MSCs, and thus the extent of therapeutic efficacy that can be achieved.

Synergistic effects of treating the spinal cord and brain in CLN1 disease.

Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1-/- ) mice before the onset of neuropathology in the brain. Various forebrain-directed gene therapy approaches have only had limited success in Ppt1-/- mice. Targeting the spinal cord via intrathecal administration of an adeno-associated virus (AAV) gene transfer vector significantly prevented pathology and produced significant improvements in life span and motor function in Ppt1-/- mice. Surprisingly, forebrain-directed gene therapy resulted in essentially no PPT1 activity in the spinal cord, and vice versa. This leads to a reciprocal pattern of histological correction in the respective tissues when comparing intracranial with intrathecal injections. However, the characteristic pathological features of INCL were almost completely absent in both the brain and spinal cord when intracranial and intrathecal injections of the same AAV vector were combined. Targeting both the brain and spinal cord also produced dramatic and synergistic improvements in motor function with an unprecedented increase in life span. These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders.

ICV galanin-like peptide stimulates non-contact erections but not touch-based erections in adult, sexually experienced male rats.

Galanin-like peptide (GALP) is a neuropeptide transcribed only within the arcuate nucleus of the hypothalamus and is thought to be a mediator between energetics and reproductive function. Intracerebroventricular (ICV) injection of GALP is known to have effects on feeding, and to significantly increase gonadotropin releasing hormone- (GnRH-) mediated luteinizing hormone (LH) secretion. Furthermore, ICV GALP is known to stimulate fos production in the medial pre-optic area (mPOA) and to a lesser extent, the paraventricular nucleus (PVN). ICV injection of 5.0nmol GALP profoundly stimulates male rat sexual behavior. It is not known if GALP's effects on sex behavior are due to an increase in appetitive or mechanical (erectile) aspects of male sexual behavior. To determine this, sexually experienced male rats were cannulated in the lateral ventricle and injected with 5.0nmol GALP or vehicle. Immediately after injections, male rats were placed in an arena connected to a second arena via a tube with a fan. The second arena contained a steroid-primed female and her bedding. The male rat had olfactory but not visual or tactile contact with the female. We analyzed the amount of time the male rats spent investigating the air intake and the number of non-contact erections (NCEs) in a 30minute test. ICV GALP significantly (p<0.05) increased both the amount of time of olfactory investigations and NCEs compared to vehicle. In a second set of animals, we tested if ICV GALP could stimulate touch-based erections. GALP had no significant effect on touch-based erections compared to vehicle. These data suggest that GALP's activation of fos within the mPOA is indicative of its action to stimulate the appetitive aspects of male sexual behavior.

Antioxidative and Neuroprotective Effects of Curcumin in an Alzheimer's Disease Rat Model Co-Treated with Intracerebroventricular Streptozotocin and Subcutaneous D-Galactose.

Epidemiological data imply links between the increasing incidences of Alzheimer's disease (AD) and type 2 diabetes mellitus. In this study, an AD rat model was established by combining treatments with intracerebroventricular streptozotocin (icv-STZ) and subcutaneous D-galactose, and the effects of curcumin on depressing AD-like symptoms were investigated. In the AD model group, rats were treated with icv-STZ in each hippocampus with 3.0 mg/kg of bodyweight once and then were subcutaneously injected with D-galactose daily (125 mg/kg of bodyweight) for 7 weeks. In the curcumin-protective group, after icv-STZ treatment, rats were treated with D-galactose (the same as in the AD model group) and intraperitoneally injected with curcumin daily (10 mg/kg of bodyweight) for 7 weeks. Vehicle-treated rats were treated as control. Compared with the vehicle control, the amount of protein carbonylation and glutathione in liver, as well as malondialdehyde in serum, were upregulated but glutathione peroxidase activity in blood was downregulated in the AD model group. The shuttle index and locomotor activity of rats in the AD model group were decreased compared with the vehicle control group. Furthermore, AD model rats showed neuronal damage and neuron loss with formation of amyloid-like substances and neurofibrillary tangles, and the levels of both ß-cleavage of AßPP and phosphorylation of tau (Ser396) were significantly increased compared with the vehicle control group. Notably, compared with the AD model group, oxidative stress was decreased and the abilities of active avoidance and locomotor activity were improved, as well as attenuated neurodegeneration, in the curcumin-protective group. These results imply the applications of this animal model for AD research and of curcumin in the treatment of AD.

Application of the Ommaya Reservoir in Managing Ventricular Hemorrhage.

BACKGROUND: Intraventricular hemorrhage (IVH) is associated with high morbidity and mortality. This study evaluated the safety and efficacy of the combined treatment of an Ommaya reservoir and conventional external ventricular drainage (EVD) using urokinase in the management of IVH. METHODS: We performed a prospective controlled study. Sixty eligible patients with IVH received conventional EVD alone (group A) or combined EVD and Ommaya reservoir (group B) between January 2010 and January 2015. Clinical, cerebrospinal fluid, and radiographic data were used to assess clot clearance, clinical outcomes, and complications between the groups. RESULTS: There were no significant differences in gender, age, blood pressure, Glasgow Coma Scale, Graeb score, intracerebral hemorrhage volume on admission, and IVH volume before surgery between groups A and B (P > 0.05). The number of injections of urokinase (20,000 IU/dose) were significantly different in group B compared with group A (P < 0.05). Repeated computed tomography scans 3 days, 6 days, and 10 days after surgery revealed that clot clearance rates at each time point were significantly increased in group B compared with group A (P < 0.05). The conventional catheter-based EVD duration time was shortened to 5 (4-6) days in group B compared with 7 (5-9) days in group A (P < 0.05). The total drainage time was prolonged to 9 (8-11) days in group B compared with 7 (5-9) days in group A (P < 0.05). Ventriculitis was not significantly different between the 2 groups (P > 0.05). The hydrocephalus incidence and mortality revealed significant differences between the 2 groups (P < 0.05). The 30-day Glasgow Outcome Scale score was significantly increased in group B compared with group A (P < 0.05). CONCLUSIONS: The combined treatment approach of an Ommaya reservoir and EVD with intraventricular urokinase is safe and effective in patients with IVH. It increased clot clearance, shortened conventional catheter-based EVD duration, prolonged total drainage time, reduced the hydrocephalus incidence and mortality, and contributed to good clinical outcomes. The Ommaya reservoir provides a safe way to increase the injection times of urokinase, which accelerated clot resolution and did not increase the risk for ventriculitis infection.

Increasing the effectiveness of intracerebral injections in adult and neonatal mice: a neurosurgical point of view.

Intracerebral injections of tracers or viral constructs in rodents are now commonly used in the neurosciences and must be executed perfectly. The purpose of this article is to update existing protocols for intracerebral injections in adult and neonatal mice. Our procedure for stereotaxic injections in adult mice allows the investigator to improve the effectiveness and safety, and save time. Furthermore, for the first time, we describe a two-handed procedure for intracerebral injections in neonatal mice that can be performed by a single operator in a very short time. Our technique using the stereotaxic arm allows a higher precision than freehand techniques previously described. Stereotaxic injections in adult mice can be performed in 20 min and have >90% efficacy in targeting the injection site. Injections in neonatal mice can be performed in 5 min. Efficacy depends on the difficulty of precisely localizing the injection sites, due to the small size of the animal. We describe an innovative, effortless, and reproducible surgical protocol for intracerebral injections in adult and neonatal mice.

Effects of ovariectomy on the inflammatory responses of female rats to the central injection of lipopolysaccharide.

It has been reported that obesity leads to more marked inflammatory responses in a site-specific manner. As has been seen in other animal models of obesity, ovariectomized rodents exhibit obesity and exacerbated fever and anorectic responses to the systemic injection of lipopolysaccharide (LPS). Furthermore, they also display increased pro-inflammatory cytokine expression in several central and peripheral tissues. Interestingly, the alterations observed in the hypothalamus are more marked than those seen in other peripheral tissues. In this study, the effects of ovariectomy on hypothalamic inflammatory responses were evaluated using the central LPS injection method. LPS was intracerebroventricularly (i.c.v.) injected into ovariectomized and gonadally intact female rats, and the immune responses of the two groups were compared. The ovariectomized rats exhibited heavier body weights than the gonadally intact rats. In addition, the ovariectomized rats displayed stronger febrile responses than the gonadally intact rats. After the i.c.v. injection of LPS, the hypothalamic interleukin (IL)-1ß, IL-6, and cyclooxygenase 2 mRNA levels of the ovariectomized rats were significantly higher than those of the gonadally intact rats. The effects of estradiol supplementation on the rats' immune responses were also examined. However, the febrile responses and hypothalamic IL-1ß, IL-6, and TNF-α mRNA levels of estradiol-supplemented ovariectomized rats and body weight matched oil-administered (control) rats did not differ after the i.c.v. injection of LPS. These results indicate that hypothalamic sensitivity to LPS is increased in ovariectomized rats and that this change is induced by the indirect effects of gonadal steroid deficiency. As is seen in other obese animal models, ovariectomy-induced obesity might play important roles in the exacerbated inflammatory responses observed in ovariectomized rats.

Nesfatin-1 induces Fos expression and elicits dipsogenic responses in subfornical organ.

Nesfatin-1 (Nes-1), an 82-amino acid protein cleaved from nucleobindin-2, has been suggested to play a role in ingestive behaviors. Intracerebroventricular (icv) injections of Nes-1 reduce water intake, although the sites of action for this effect are not known. Two series of experiments were done to identify potential sites of action of Nes-1 in drinking behavior. In the first series, icv injections of Nes-1 were made in urethane-anesthetized rats to investigate the distribution of neurons containing Fos-like immunoreactivity (Fos-ir) within the forebrain. Circumventricular organs, including subfornical organ (SFO), were found to contain neurons expressing Fos-ir. Additionally, several hypothalamic, thalamic and limbic nuclei also contained Fos-labeled neurons. As SFO is a pivotal central site in the regulation of water intake, a second series of experiments was done to investigate the role of direct injections of Nes-1 into SFO on water intake in conscious, freely moving rats. Nes-1 (2pmol) injections into SFO induced an increase in water intake compared to vehicle injections. However, when food was made available for ingestion after the Nes-1 injection, the dipsogenic effects of Nes-1 were attenuated. Additionally, the drinking response to Nes-1 was found to be more potent than that observed after injections of ANG II into SFO. Neither simultaneous injections ANG II nor the ANG II type-1 receptor blocker losartan affected the Nes-1 dipsogenic response. Taken together, these results suggest that Nes-1 is a potent dipsogenic agent in SFO, and that Nes-1 may act independently of the SFO angiotensinergic system to elicit the dipsogenic effect.

Intraventricular baclofen as an alternative to intrathecal baclofen for intractable spasticity or dystonia: outcomes and technical considerations.

OBJECT: The aim of this study was to identify the benefits of intraventricular baclofen (IVB) therapy for the treatment of intractable spasticity or dystonia in a subset of patients who had experienced multiple revisions while receiving intrathecal baclofen (ITB) therapy. METHODS: The authors reviewed the charts of 22 consecutive patients with intractable spasticity or dystonia who initially underwent ITB therapy, subsequently suffered multiple revisions during ITB therapy, and ultimately received IVB therapy, all during a 12-year period from November 1998 to October 2010. The intraventricular catheters were positioned in the lateral ventricle, aided by stereonavigation. RESULTS: The surgical revision rate (the average number of surgical revisions per average number of follow-up years) during ITB therapy was 0.84, and was 0.50 during IVB therapy. The most frequent complication requiring surgical revision during ITB therapy was catheter occlusion, followed by pump malfunction/pump pocket issues, and infection. The most frequent complication requiring surgical revision during IVB therapy was infection, followed by catheter misplacement/migration. Four patients suffered infection that required removal of their intraventricular catheter, and currently have no baclofen system. CONCLUSIONS: Some of these patients had a history of increasing revisions with increasing frequency during ITB therapy. Such a history puts them at risk for spinal arachnoiditis, a condition that complicates further ITB therapy. For such patients, the authors believe that IVB therapy may be a beneficial therapeutic option, given that the surgical revision rate was lower for IVB than for ITB. Intraventricular baclofen may be a cost-effective option for patients with mounting revisions during ITB therapy.

Stem cells based therapy in high grade glioma: why the intraventricular route should be preferred?

AIM: Mesenchymal stem cells (MSCs) migrate in response to chemokines and possess extensive tropism for experimental glioma. Antitumor effects have been reported following intracranial and intravenous administration of gene-modified MSCs. Among the different routes for cell transplant, the intraventricular (IV) approach found very little employment in comparison with intraparenchymal, intratumoral and intravenous administration protocols. Nevertheless, IV transplantation offers advantages in terms of cells viability and distribution toward target sites, opening interesting opportunities for its clinical application. METHODS: Using a rat glioma model, we investigated migratory capacity, tumor tropism, distribution and differentiation of MSCs following IV administration. RESULTS: Transplanted MSCs create niches of viable cells in the subventricular zone and can be stimulated to migrate to sites of tumor infiltration. MSCs seemed not to be involved in tumor growth and angiogenesis. CONCLUSION: We speculate that the IV route can be used to achieve a kind of reservoir of self-renewal cells, potentially active against the spread of cancer cells. Further studies are needed to shed light on MSCs distribution close to the ventricular wall, in order to define their lifespan and their capacity to migrate towards new-enhancing foci time after implantation.

Stem cell transplantation into the intraventricular space via an Ommaya reservoir in a patient with amyotrophic lateral sclerosis.

Stem cells have been highlighted for a possible clinical trial in amyotrophic lateral sclerosis (ALS), and have been employed in SOD1 mice and ALS patients. Human trials for stem cell transplantations have used intrathecal route by lumbar puncture. However, stem cells introduced via lumbar injection would tend to sink downwards rather than ascending to the brain and cervical and thoracic spinal cord. Therefore, we adopted for intraventricular injection via an Ommaya reservoir, and wished to test the practicality of intraventricular stem cell injection in ALS. In the case presented autologous mesenchymal stromal cells (MSCs) were isolated from the bone marrow of a male patient with ALS who underwent insertion of an Ommaya reservoir. Expanded MSCs (hBM-MSCs: dose of 1 X 106 cells/kg) were suspended in autologous CSF and directly transplanted into the ALS patient's lateral ventricle via the Ommaya reservoir. Clinical, laboratory, and radiographic evaluation of the patient revealed no serious adverse effects related to the stem cell therapy. Intraventricular injection with an optimized number of cells is safe, and is a potential route for stem cell therapy in patients with ALS. Intraventricular injection via an Ommaya reservoir makes repetitive injection of stem cells easy and reliable even in far advanced ALS patients.

Interleukin-1ß increases release of endothelin-1 and tumor necrosis factor as well as reactive oxygen species by peripheral leukocytes during experimental subarachnoid hemorrhage.

In the subarachnoid hemorrhage (SAH) blood mixes with cerebrospinal fluid, what starts immunoinflammatory processes - increased synthesis of proinflammatory cytokines, and formation of reactive oxygen species (ROS), resulting in pre-activation of different populations of peripheral leukocytes. Migration of leukocytes to the brain parenchyma through broken blood brain barrier may produce extra brain tissue injury besides of that resulting from SAH. We examined in adult rats the effect of interleukin-1ß (IL-1ß) neutralization on secretion of cytokines as well as production of ROS in the course of SAH. SAH was produced by injection of 150 µL of autologous arterial blood into cisterna magna. In 50% of animals, IL-1beta activity was inhibited by intracerebroventricular administration of anti-rat IL-1ß antibodies. Ninety minutes or 24 hrs following surgery, blood samples were drawn from the extraorbital plexus and centrifuged to obtain two leukocyte subpopulations - polymorphonuclear (PMN) and mononuclear (MN). The chemiluminescence, a hallmark of ROS synthesis, was measured in PMNs. In supernatants from MNs cultures, concentrations endothelin-1 (ET-1), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were assessed. SAH caused the increase ofn PMNs chemiluminescence as well as the increase of production of ET-1 and TNF-α by MNs but had no influence on IL-6 concentration. Neutralization of IL-1ß resulted in significant decrease of chemiluminescence as well as concentration of both ET-1 and TNF-α, while IL-6 concentration was increased. These revealed an important role of IL-1ß in the activation of peripheral leukocytes in the course of subarachnoid hemorrhage.

Intracerebroventricular opioids for intractable pain.

When pain is refractory to systemic opioid and non-opioid analgesic therapy and palliative chemoradiation or ablative or stimulant neurosurgical procedures are not possible, palliative treatment becomes limited, particularly if the patient wishes to be at home at the end of life. Intracerebroventricular (ICV) infusion of morphine in the home setting might be presented as an option. The present article reviews the basic and clinical evidence of the efficacy and safety of ICV administration of opioids. Information was gathered from various bibliographic sources, including PubMed and others, and summarized and evaluated to assess the efficacy and safety of ICV opioids for pain relief. Results from ICV infusion of morphine into terminally ill patients refractory to other pain treatments have been reported since the early 1980s. Good efficacy has been achieved for the vast majority of patients, without serious development of analgesic tolerance. There have also been a low incidence of adverse effects, such as constipation and respiratory depression, and a significant retention of alertness associated with this route of administration. Intracerebroventricular infusion of opioid analgesics thus appears to be a safe and effective therapy for the palliative treatment of refractory pain.