Journal of Neurodegeneration and Regeneration

Complete JNDR Vol. 4, No. 1 Issue

. . — Thu, 25 Jul 2013 00:00:00 -0400

Do metabolites of polymethylcyclosiloxanes induce physiological disorders?

Bernhard Buchter, Dr. sc. techn. Dipl. Forsting, Margrit Dunkel, BScOT AOTR — Thu, 25 Jul 2013 00:00:00 -0400

Polydimethylcyclosiloxanes are synthetic organo-silicon compounds used in everyday products. Their degradation in humans is not completely understood. Dimethylsilanediol as the final metabolite is debatable. Silicon has never been directly monitored, even though complete mineralisation to carbon dioxide and silicon dioxide is likely. The latter one is not respirable, not degradable, and hardly soluble and is hence presumably accumulated within the human body. Chemical similarity to dimethylsulfoxide suggests that dimethylsilanediol is able to penetrate the intact skin and to pass the blood-brain barrier. Degradation within the brain could lead to increased levels of formic acid and silicon deposits visible as plaques. Intermediate and final metabolites may disturb the synthesis of citrate, succinate and fumarate. They may induce and boost also many of today’s autoimmune diseases like Alzheimer’s disease, Parkinson’s disease, systemic sclerosis, amyotrophic lateral sclerosis, primary biliary cirrhosis, obesity, and multiple sclerosis. In view of the possible impact of carbon-silicon compounds on human health, their metabolic pathways have to be unambiguously elucidated based on separate directly determined mass balances of carbon and silicon.

Keywords: Alumosilicate, Alzheimer’s disease, Blood-brain barrier, Citric acid circle, Dimethylsilanediol, Dimethylsulfoxide, Diabetes mellitus, Dopamine, Formic acid, Fumarate, Mitochondria, Obesity, Parkinson’s disease, Plaques, Primary biliary cirrhosis, Psoriasis, Sclerosis

DOI:10.5055/jndr.2013.0007

A rat model of spinal cord ischemic injury

Thu, 25 Jul 2013 00:00:00 -0400

There is a need of ischemic model of spinal cord injury to identify the therapeutic window for intervention of ischemic injury in humans. Calcium for long has been known to be a key source of neuronal damage during ischemic injury. The purpose of this study is to develop an in vivo model of spinal cord ischemia in rats and to confirm the functionality of the model by studying the expression pattern of inositol 1,4,5-triphosphate receptor isoform 1 (IP3R1) and ryanodine receptor isoform 2 (RyR2). Ischemic injury was induced by clamping the aorta below the azygous vein using thoracotomy approach for 27 minutes. Behavioral and histopathologic studies were done at 0, 2, 4, 8, and 48 hours after injury. Eighteen rats suffered from complete paralysis and two showed perceptible movement of the joints of their hind limbs. There was no paralysis in five animals (Sham Group). Histopathology with hemotoxylin and eosin stain at 8 and 48 hours demonstrated neuronal cell loss and diffused neuronal necrosis. Glial fibrillary acidic protein staining showed severe reactive gliosis. Apoptosis was also visualized at 48 hours of ischemia. Expression of IP3R1 and RyR2 was upregulated after ischemic injury and expression of RyR2 increased until 8 hours after injury, while the maximum expression of IP3R1 was observed 4 hours after injury. This preliminary study confirmed that this model of ischemic spinal cord injury causes paralysis and significant changes in neurology and histopathology with time. Increased expression of IP3R1 and RyR2 confirms the functionality of the model by showing increased intracellular calcium levels.

Keywords: Calcium, Ischemic injury, Spinal cord, Rat model

DOI:10.5055/jndr.2013.0008

Delayed functional recovery in presymptomatic mSOD1G93A mice following facial nerve crush axotomy

Thu, 25 Jul 2013 00:00:00 -0400

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive loss of motoneurons (MN). Axonal pathology and presynaptic deafferentation precede MN degeneration during disease progression in patients and the ALS mouse model (mSOD1). Previously, we determined that a functional adaptive immune response is required for complete functional recovery following a facial nerve crush axotomy in wild-type (WT) mice. In this study, we investigated the effects of facial nerve crush axotomy on functional recovery and facial MN survival in presymptomatic mSOD1 mice, relative to WT mice. The results indicate that functional recovery and facial MN survival levels are significantly reduced in presymptomatic mSOD1, relative to WT, and similar to what has previously been observed in immunodeficient mice. It is concluded that a potential immune system defect exists in the mSOD1 mouse that negatively impacts neuronal survival and regeneration following target disconnection associated with peripheral nerve axotomy.

Keywords: Motoneuron survival, Functional recovery, Axotomy, SOD1, ALS

DOI:10.5055/jndr.2013.0009

Neuroprotective effects of bone marrow stromal cells in cocultures of fetal dopaminergic neuronal cultures

Thu, 25 Jul 2013 00:00:00 -0400

Objective: The primary objective was to compare the neuroprotection conferred by diffusible factors to those mediated by direct cell-cell contacts in cocultures of bone marrow stromal cells (BMSC) and dopaminergic (DA) neurons treated with methyl-phenyl-pyridinium (MPP+).

Methods: Fetal midbrain (MB) cell cultures of DA neurons were cocultured directly with green fluorescent protein (GFP+)-expressing BMSC or in bilayer cultures separated by a 0.4-µm pore semipermeable membrane. Endpoints of toxicity included survival of tyrosine hydroxylase (TH+) immunoreactive cells, lengths of the TH+ neurites, and [3H]-DA uptake. Neurotrophic factors released into media were measured. A number of cells coexpressing GFP+ and neuronal markers were counted to assess possible fusion with or transdifferentiation into DA neurons.

Results: DA neurons in cocultures (mixed and bilayer) sustained significantly less damage compared to the effects of MPP+ on MB monolayer cultures. Neurite length and [3H]-DA uptake were significantly greater in bilayer cultures than in monolayer MB cell cultures. Mixed cocultures (with MB and GFP+ BMSC in direct contact) were also protected against MPP+. Levels of glial cell-derived neurotrophic factor were found to be elevated in the bilayer culture media. There were no TH+ cells that coexpressed GFP, but 7-10 percent of neurons coexpressed GFP and neuron-specific nuclear antigen suggesting possible fusion of GFP+ BMSC with non-TH+ neurons.

Conclusion: Neuroprotection was observed to an equal extent in both mixed cultures and bilayer cultures in which MB and BMSC cultures were separated by a membrane. Therefore, diffusible factors elaborated by BMSC are sufficient for mitigating neurotoxicity to DA neurons.

Keywords: Mesenchymal stem cells, Methyl-phenyl-pyridinium, Growth factors, Cell fusion

DOI:10.5055/jndr.2013.0010

Topiramate increases local proinflammatory cytokine gene expression after nerve crush lesion in rats exclusively in injured nerves

Nurcan Üçeyler, MD, Stefan Bischofs, MD, Claudia Sommer, MD — Thu, 25 Jul 2013 00:00:00 -0400

Topiramate (TPM) is an anticonvulsant and putative neuroprotective drug. As some older anticonvulsants were shown to modulate cytokine expression, the authors investigated whether TPM influences injury-induced cytokine expression in the sciatic nerve and the L4/5 dorsal root ganglia (DRG) of rats. Twenty-five rats 12 and 24 hours after sciatic nerve crush lesion were investigated. Using quantitative real-time polymerase chain reaction, the gene expression of the proinflammatory cytokines tumor necrosis factor-alpha (TNF), its receptors 1 and 2 (TNFR1 and TNFR2), interleukin (IL)-1β, and IL-6 and the gene expression of the anti-inflammatory cytokines IL-10 and transforming growth factor-beta (TGFβ) were measured. In sciatic nerves, the gene expression of all cytokines and TNFR1 and TNFR2 peaked 12 hours after surgery except for IL-6 which had its maximum at 24 hours. The TPM effect was restricted to injured nerves: TPM increased gene expression of TNF (×3), IL-6 (×2.2), and IL-1β (×1.4), whereas decreased gene expression of IL-10 (×0.7). The authors propose that TPM influences cytokine gene expression by acting on Schwann cells in the injured nerve.

Keywords: Topiramate, Sciatic nerve crush, Proinflammatory cytokines, Anti-inflammatory cytokines

DOI:10.5055/jndr.2013.0011

Tuberous sclerosis complex a paradigm for studying adult neurogenesis and brain tumors

Philippe Taupin, PhD — Thu, 25 Jul 2013 00:00:00 -0400

Tuberous sclerosis complex (TSC) is a relatively rare genetic disease characterized by the formation of benign tumors or hamartomas in multiple organs. The tumors are noninvasive and rarely transform to metastatic lesions. TSC is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes. Neurologically, individuals with TSC have severe complications, including refractory seizures, autism, mental retardation, learning difficulties, and changes in behavior. Tubers in the cerebral cortex, subependymal nodules (SENs) along the lateral walls of the lateral ventricles, and subependymal giant cell (GC) astrocytomas are characteristic brain lesions in patients with TSC. Astrocytic-like cells immunopositive for both glial and neuronal markers, dysplastic neurons (DNs), and GCs immunopositive for nestin and vimentin, as well as for proliferation markers such as proliferating nuclear cell antigen (PCNA) and Ki-67, are histological hallmarks of the disease. DNs and GCs retain their ability to re-enter the cell cycle and are immunopositive for markers of neural progenitor and stem cells. Neurogenesis occurs in the adult brain of mammals, particularly in the hippocampus and subventricular zone (SVZ). In the SVZ, newly generated neuronal cells migrate along the ventricle and a SVZ origin for brain tumors in the adult brain have been reported. These brain tumors express markers of neural progenitor and stem cells. The study of analogies and differences between SENs in TSC, neurogenesis in the SVZ, and tumors in the adult brain would reveal clues on the development and origin of SENs and brain tumors.

Keywords: Epilepsy, Cancer, Drug, Disease, Neural stem cells, Rapamycin, Therapy, Tumor

DOI:10.5055/jndr.2013.0012