[Show abstract][Hide abstract] ABSTRACT: According to the traditional understanding of cerebrospinal fluid (CSF) physiology, the majority of CSF is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi. This review surveys key developments leading to the traditional concept. Challenging this concept are novel insights utilizing molecular and cellular biology as well as neuroimaging, which indicate that CSF physiology may be much more complex than previously believed. The CSF circulation comprises not only a directed flow of CSF, but in addition a pulsatile to and fro movement throughout the entire brain with local fluid exchange between blood, interstitial fluid, and CSF. Astrocytes, aquaporins, and other membrane transporters are key elements in brain water and CSF homeostasis. A continuous bidirectional fluid exchange at the blood brain barrier produces flow rates, which exceed the choroidal CSF production rate by far. The CSF circulation around blood vessels penetrating from the subarachnoid space into the Virchow Robin spaces provides both a drainage pathway for the clearance of waste molecules from the brain and a site for the interaction of the systemic immune system with that of the brain. Important physiological functions, for example the regeneration of the brain during sleep, may depend on CSF circulation.
Fluids and Barriers of the CNS 05/2014; 11(1):10. DOI:10.1186/2045-8118-11-10
[Show abstract][Hide abstract] ABSTRACT: Peptides have a great potential for the treatment of neurological disorders, but the clinical translation is still facing significant hurdles. Delivery issues are among them: for example the short systemic half-life of peptides, poor passage across the blood brain barrier, slow diffusion through the extracellular space and rapid cerebrospinal fluid washout. This review will discuss new findings on the blood brain barrier and the physiology of the cerebrospinal fluid system, which may be relevant for the delivery of peptides to the brain. It will also discuss delivery issues and opportunities related to different administration routes, i.e. intravenous, intraventricular and intracerebral. Lastly, we summarize stem cell-based approaches; such cell therapy relies on the secretion of soluble factors, i.e. peptides. We highlight approaches to use encapsulated, genetically engineered cells as a vehicle for sustained delivery of peptides to the diseased brain.
Current Medicinal Chemistry 02/2014; 21(23). DOI:10.2174/0929867321666140217124349 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In our study we examined acute and chronic changes in c-Fos expression patterns in the visual system of the rat after complete visual deafferentation. In 20 male Lewis rats, the retro-bulbar part of the optic nerve was sectioned bilaterally. Ten animals underwent c-Fos immunohistochemistry after 3 days and 10 animals after 3 weeks examining time-dependent changes. The control group consisted of 10 animals, which did not undergo any surgical manipulation. c-Fos expression in the rat visual system experienced significant changes after acute and chronic bilateral complete visual deafferentation. Acute decrease in c-Fos level was observed in the ventral lateral geniculate nucleus, intergeniculate leaflet, superficial gray layer of the superior colliculus and layers IV and V of the primary visual cortex. After chronic deafferentation, c-Fos expression was also found to be decreased in the optic and deep layers of the superior colliculus and layer VI of the primary visual cortex. No change in c-Fos expression was observed in the dorsal lateral geniculate nucleus and layers I, II and III of the primary visual cortex. This work shows that secondary complete blindness does not lead to uniform decrease in c-Fos levels in all subcortical and cortical brain regions related to vision. These findings provide important information concerning expression of the immediate-early gene product c-Fos in secondary blind rodent models. It may further serve as a relevant baseline finding when electrical stimulation of the visual system is performed, aiding the assessment of visual neuroprosthesis using c-Fos as a functional mapping tool when evaluating different stimulus parameters in blind rodent models.
Experimental Brain Research 07/2013; 229(4). DOI:10.1007/s00221-013-3623-0 · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: As pharmacological therapies have largely failed so far, stem cell therapy has recently come into the focus of ALS research. Neuroprotective potential was shown for several types of stem and progenitor cells, mainly due to release of trophic factors. In the present study, we assessed the effects of intracerebroventricular injection of glucagon-like peptide 1 (GLP-1) releasing mesenchymal stromal cells (MSC) in mutant SOD1 (G93A) transgenic mice.
To improve the neuroprotective effects of native MSC, they had been transfected with a plasmid vector encoding a GLP-1 fusion gene prior to the injection, as GLP-1 was shown to exhibit neuroprotective properties before. Cells were encapsulated and therefore protected against rejection. After intracerebroventricular injection of these GLP-1 MSC capsules in presymptomatic SOD1 (G93A) mice, we assessed possible protective effects by survival analysis, measurement of body weight, daily monitoring and evaluation of motor performance by rotarod and footprint analyses. Motor neuron numbers in the spinal cord as well as the amount of astrocytosis, microglial activation, heat shock response and neuronal nitric oxide synthase (nNOS) expression were analyzed by immunohistological methods. Treatment with GLP-1 producing MSC capsules significantly prolonged survival by 13 days, delayed symptom onset by 15 days and weight loss by 14 days and led to significant improvements in motor performance tests compared to vehicle treated controls. Histological data are mainly in favour of anti-inflammatory effects of GLP-1 producing MSC capsules with reduced detection of inflammatory markers and a significant heat shock protein increase.
Intracerebroventricular injection of GLP-1 MSC capsules shows neuroprotective potential in the SOD1 (G93A) mouse model.
PLoS ONE 06/2012; 7(6):e36857. DOI:10.1371/journal.pone.0036857 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Amyloid accumulation in the brain parenchyma is a hallmark of Alzheimer's disease (AD) and is seen in normal aging. Alterations in cerebrospinal fluid (CSF) dynamics are also associated with normal aging and AD. This study analyzed CSF volume, production and turnover rate in relation to amyloid-beta peptide (Aβ) accumulation in the aging rat brain.
Aging Fischer 344/Brown-Norway hybrid rats at 3, 12, 20, and 30 months were studied. CSF production was measured by ventriculo-cisternal perfusion with blue dextran in artificial CSF; CSF volume by MRI; and CSF turnover rate by dividing the CSF production rate by the volume of the CSF space. Aβ40 and Aβ42 concentrations in the cortex and hippocampus were measured by ELISA.
There was a significant linear increase in total cranial CSF volume with age: 3-20 months (p < 0.01); 3-30 months (p < 0.001). CSF production rate increased from 3-12 months (p < 0.01) and decreased from 12-30 months (p < 0.05). CSF turnover showed an initial increase from 3 months (9.40 day-1) to 12 months (11.30 day-1) and then a decrease to 20 months (10.23 day-1) and 30 months (6.62 day-1). Aβ40 and Aβ42 concentrations in brain increased from 3-30 months (p < 0.001). Both Aβ42 and Aβ40 concentrations approached a steady state level by 30 months.
In young rats there is no correlation between CSF turnover and Aβ brain concentrations. After 12 months, CSF turnover decreases as brain Aβ continues to accumulate. This decrease in CSF turnover rate may be one of several clearance pathway alterations that influence age-related accumulation of brain amyloid.
Fluids and Barriers of the CNS 01/2012; 9(1):3. DOI:10.1186/2045-8118-9-3
[Show abstract][Hide abstract] ABSTRACT: Chemotherapeutic drug-eluting beads (DEBs) are microspheres that are in clinical use for intraarterial chemoembolisation of liver cancer. Here we report on the biocompatibility and anti-tumour efficacy of DEBs after intratumoral application in a rat BT4Ca glioma model.
Doxorubicin and irinotecan-eluting DEBs were suspended in a Ca(2+)-free aqueous alginate solution that provides a sol-gel transition when injected into the Ca(2+) rich brain tissue. In this way the DEBs are immobilised at the implantation site. Forced elution studies in vitro using a USP-4 flow-through apparatus demonstrated that the alginate excipient helped to reduce the burst effect and rate the elution from the beads. From the in vivo evaluation, doxorubicin DEBs demonstrated a significant local toxicity, while irinotecan-loaded DEBs showed good local tissue compatibility. Doxorubicin at higher concentrations and irinotecan-loaded DEBs were found to decrease tumour volume, increase survival time and decrease the Ki67 proliferation index of the tumour. Doxorubicin was shown by fluorescent microscopy to diffuse into the peritumoral tissue, but also penetrates along white matter tracts, to more distant areas.
We conclude that the alginate suspension of irinotecan DEBs can be considered safe and effective in a clinical setting.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE Previous research in a rat glioma model has shown that the local intratumoral application of polymerbased drug-eluting beads (DEBs) loaded with doxorubicin or irinotecan suppress tumour growth and prolong survival. For translation into a clinical setting, the present experiment investigates in the healthy cat brain the local and systemic toxicity of a multiple injection shot technique. METHODS Three injection shots were placed, each at a 1 cm distance in the frontal lobe. The DEBs were suspended in an aqueous alginate excipient solution, which becomes subject to a sol-gel transition when injected into the Ca(2+)- rich brain tissue environment. Systemic and local side effects were monitored over a period of two weeks. Injection sites were histologically investigated. RESULTS Gelling of the alginate results in the permanent immobilisation of the microspheres at the implantation site. A distinct local cytotoxic effect of doxorubicin was found with intracerebral and intraventricular haemorrhages, and signs of brain tissue necrosis. In cats injected with irinotecan DEBs, such local adverse side effects did not occur. No signs of systemic toxicity were found with both chemotherapeutics. DISCUSSION We conclude that the multiple injection shot technique with irinotecan DEBs meets feasibility criteria and safety requirements for a clinical application.
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury remains a major cause of death and disability; it is estimated that annually 10 million people are affected. Preclinical studies have shown the potential therapeutic value of stem cell therapies. Neuroprotective as well as regenerative properties of stem cells have been suggested to be the mechanism of action in preclinical studies. However, up to now stem cell therapy has not been studied extensively in clinical trials. This article summarizes the current experimental evidence and points out hurdles for clinical application. Focusing on a cell therapy in the acute stage of head injury, the potential of encapsulated cell biodelivery as a novel cell-therapeutic approach will also be discussed.
Dialogues in clinical neuroscience 08/2011; 13(3):279-86.
[Show abstract][Hide abstract] ABSTRACT: Human mesenchymal stem cells (MSC) are promising candidates for cell therapy of neurological diseases. However, co-transplantation of MSC with tumour cell lines has been reported to promote tumour growth. In this study, we co-transplant glioma cells together with alginate-encapsulated MSC. Immunocompetent BD-IX rats were inoculated with syngeneic BT4Ca glioma cells. Encapsulated unmodified MSC, endostatin producing (endoMSC) or cell-free alginate capsules were stereotactically implanted into the tumour bed. After 12 days, tumour volumes were significantly diminished in the MSC-treated group. The decrease in tumour volume found with endoMSC was statistically not significant, despite significantly reduced tumour vascularization. We conclude that, under syngeneic conditions in the immunocompetent animal, (1) the intracranial, orthotopic co-transplantation of MSC with glioma cells leads to a suppression in tumour growth and (2) the tumour can escape the antiangiogenic treatment with endostatin. Our finding may facilitate the clinical translation of encapsulated cell therapy.
Journal of Microencapsulation 07/2011; 28(7):621-7. DOI:10.3109/02652048.2011.599441 · 1.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Encapsulated human mesenchymal stem cells(MSC) are studied in a double transgenic mouse model of Alzheimer's disease (AD) after intraventricular implantation at 3 months of age. Abeta 40/42 deposition, and glial (GFAP) and microglial (CD11b) immunoreactivity were investigated 2 months after transplantation of either native MSC or MSC transfected with glucagon-like peptide-1 (GLP-1). CD11b immunostaining in the frontal lobes was significantly decreased in the GLP-1 MSC group compared to the untreated controls. Also, the plaque associated GFAP immunoreactivity was only observed in one of four animals in the GLP-1 MSC group. Abeta 40 whole brain ELISA was decreased in the MSC group: 86.06±5.2 pg/ml (untreated control) vs. 78.67±11.2 pg/ml (GLP-1 MSC group) vs.70.9±11.1 pg/ml (MSC group, p<0.05). Intraventricular transplantation of native and GLP-1 transfected MSC has been shown effective. Decreased amyloid deposition or suppression of glial and microglial responses were observed. However, encapsulation of MSC may alter their biological activity.
[Show abstract][Hide abstract] ABSTRACT: Neuropeptides may have considerable potential in the treatment of acute and chronic neurological diseases. Encapsulated genetically engineered cells have been suggested as a means for sustained local delivery of such peptides to the brain. In our experiments, we studied human mesenchymal stem cells which were transfected to produce glucagon-like peptide-1 (GLP-1).
Cells were packed in a water-permeable mesh bag containing 400 polymeric microcapsules, each containing 3000 cells. The mesh bags were either transplanted into the subdural space, into the brain parenchyma or into the cerebral ventricles of the cat brain. Mesh bags were explanted after two weeks, and cell viability, as well as GLP-1 concentration in the cerebrospinal fluid (CSF), was measured.
Viability of cells did not significantly differ between the three implantation sites. However, CSF concentration of GLP-1 was significantly elevated only after ventricular transplantation with a maximum concentration of 73 pM (binding constant = 70 pM).
This study showed that ventricular cell-based delivery of soluble factors has the capability to achieve concentrations in the CSF which may become pharmacologically active. Despite the controversy about the pharmacokinetic limitations of ventricular drug delivery, there might be a niche in this for encapsulated cell biodelivery of soluble, highly biologically-effective neuropeptides of low molecular weight like GLP-1.
Fluids and Barriers of the CNS 05/2011; 8(1):18. DOI:10.1186/2045-8118-8-18
[Show abstract][Hide abstract] ABSTRACT: Despite some progress in therapy, the prognosis of patients with malignant gliomas remains poor. Local delivery of cytostatics to the tumour has been proven to be an efficacious therapeutic approach but which nevertheless needs further improvements. Drug Eluting Beads (DEB), have been developed as drug delivery embolisation systems for use in trans-arterial chemoembolisation. We tested in a rat model of malignant glioma, whether DEB, loaded with doxorubicin or irinotecan, may be used for local treatment of brain tumours. Unloaded and drug loaded DEB were implanted into the brains of healthy and tumour bearing BD IX rats followed by histological investigations and survival assessment. Intracerebral implantation of unloaded DEB caused no significant local tissue damage, whilst both doxorubicin and irinotecan DEB improved survival time significantly. However, a significant local toxicity was found after the implantation of doxorubicin DEB but not with irinotecan DEB. We concluded that irinotecan appears to be superior in terms of the risk-benefit ratio and that DEB may be used for local treatment of brain tumours.
Journal of Materials Science Materials in Medicine 02/2010; 21(4):1393-402. DOI:10.1007/s10856-009-3803-4 · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: "Naked" human mesenchymal stem cells (MSC) are neuro-protective in experimental brain injury (TBI). In a controlled cortical impact (CCI) rat model, we investigated whether encapsulated MSC (eMSC) act similarly, and whether efficacy is augmented using cells transfected to produce the neuro-protective substance glucagon-like peptide-1 (GLP-1).
Thirty two Sprague-Dawley rats were randomized to five groups: controls (no CCI), CCI-only, CCI+eMSC, CCI+GLP-1 eMSC, and CCI+empty capsules. On day 14, cisternal cerebro-spinal fluid (CSF) was sampled for measurement of GLP-1 concentration. Brains were immuno-histochemically assessed using specific antibody staining for NeuN, MAP-2 and GFAP. In another nine healthy rats, in vitro.
GLP-1 production rates were measured from cells explanted after 2, 7 and 14 days. GLP-1 production rate in transfected cells, before implantation, was 7.03 fmol/capsule/h. Cells were still secreting GLP-1 at a rate of 3.68+/-0.49, 2.85+/-0.45 and 3.53+/-0.55 after 2, 7 and 14 days, respectively. In both of the stem cell treated CCI groups, hippocampal cell loss was reduced, along with an attenuation of cortical neuronal and glial abnormalities, as measured by MAP-2 and GFAP expression. The effects were more pronounced in animals treated with GLP-1 secreting eMSC. This group displayed an increased CSF level of GLP-1 (17.3+/-3.4pM).
Hippocampal neuronal cell loss, and cortical glial and neuronal cyto-skeletal abnormalities, after CCI are reduced following transplantation of encapsulated eMSC. These effects were augmented by GLP-1 transfected eMSC.