Manifestations of Apprehension and Anxiety in a Sprague Dawley Cranial Defect Model.

BACKGROUND: Syndrome of the trephined is a neurologic condition that commonly arises in patients who undergo craniectomy and have a prolonged cranial defect. Symptoms of this condition include headache, difficulties concentrating, diminished fine motor/dexterity skills, mood changes, and anxiety/apprehension. The authors hypothesize that an animal model demonstrating anxiety/apprehension in rats who undergo craniectomy is feasible utilizing standardized animal behavioral testing. METHODS: Sprague Dawley rats were the stratified to 1 of 2 groups for comparison of neurobehavioral outcomes. Group #1 (closed cranial group) had their cranial trephination immediately closed with acrylic to restore normal cranial anatomy and Group #2 (open cranial group) had their cranial trephination enlarged to represent a decompressive hemicraniectomy immediately. Anxiety/apprehension was studied using a standardized rodent open field test. Statistical comparison of differences among the 2 groups was performed. RESULTS: Ten rats were studied with 5 rats in each group. Standard rodent open field testing of anxiety demonstrated no difference among the 2 groups at 1 week. Rats in the "Open cranial group" demonstrated progressively more anxiety over the following 3-month period. Rats in the "Open cranial group" demonstrated increasing anxiety levels as compared with rats in the "Closed cranial group." At week 16, the "Open cranial group" anxiety levels were significantly greater than week 4 (t = 2.24, P = 0.04) demonstrating a significant linear trend over time (R = 0.99; P = 0.002). The "Closed cranial group" did not show this trend (R = 07; P = 0.74). CONCLUSION: Our study demonstrates that anxiety and apprehension are more prevalent in rats with an open, prolonged cranial defect in comparison to those with a closed cranium. This correlates with similar finds in humans with syndrome of the trephined.

Aspirin and multiple sclerosis.

Aspirin is widely used to lessen the risks of cardiovascular events. Some studies suggest that patients with multiple sclerosis have an increased risk for some cardiovascular events, for example, venous thromboembolism and perhaps ischemic strokes, raising the possibility that aspirin could lessen these increased risks in this population or subgroups (patients with limited mobility and/or antiphospholipid antibodies). However, aspirin causes a small increased risk of hemorrhagic stroke, which is a concern as it could potentially worsen a compromised blood-brain barrier. Aspirin has the potential to ameliorate the disease process in multiple sclerosis (for example, by limiting some components of inflammation), but aspirin also has the potential to inhibit mitochondrial complex I activity, which is already reduced in multiple sclerosis. In an experimental setting of a cerebral ischemic lesion, aspirin promoted the proliferation and/or differentiation of oligodendrocyte precursors, raising the possibility that aspirin could facilitate remyelination efforts in multiple sclerosis. Other actions by aspirin may lead to small improvements of some symptoms (for example, lessening fatigue). Here we consider potential benefits and risks of aspirin usage by patients with multiple sclerosis.

Exploring Whether Iron Sequestration within the CNS of Patients with Alzheimer's Disease Causes a Functional Iron Deficiency That Advances Neurodegeneration.

The involvement of iron in the pathogenesis of Alzheimer's disease (AD) may be multifaceted. Besides potentially inducing oxidative damage, the bioavailability of iron may be limited within the central nervous system, creating a functionally iron-deficient state. By comparing staining results from baseline and modified iron histochemical protocols, iron was found to be more tightly bound within cortical sections from patients with high levels of AD pathology compared to subjects with a diagnosis of something other than AD. To begin examining whether the bound iron could cause a functional iron deficiency, a protein-coding gene expression dataset of initial, middle, and advanced stages of AD from olfactory bulb tissue was analyzed for iron-related processes with an emphasis on anemia-related changes in initial AD to capture early pathogenic events. Indeed, anemia-related processes had statistically significant alterations, and the significance of these changes exceeded those for AD-related processes. Other changes in patients with initial AD included the expressions of transcripts with iron-responsive elements and for genes encoding proteins for iron transport and mitochondrial-related processes. In the latter category, there was a decreased expression for the gene encoding pitrilysin metallopeptidase 1 (PITRM1). Other studies have shown that PITRM1 has an altered activity in patients with AD and is associated with pathological changes in this disease. Analysis of a gene expression dataset from PITRM1-deficient or sufficient organoids also revealed statistically significant changes in anemia-like processes. These findings, together with supporting evidence from the literature, raise the possibility that a pathogenic mechanism of AD could be a functional deficiency of iron contributing to neurodegeneration.

Substrate Reduction Therapy for Krabbe Disease: Exploring the Repurposing of the Antibiotic D-Cycloserine.

Krabbe disease is a lysosomal storage disease that is caused by a deficiency in galactosylceramidase. Infantile onset disease is the most common presentation, which includes progressive neurological deterioration with corresponding demyelination, development of globoid cells, astrocyte gliosis, etc. Hemopoietic stem cell transplantation (HSCT) is a disease modifying therapy, but this intervention is insufficient with many patients still experiencing developmental delays and progressive deterioration. Preclinical studies have used animal models, e.g., twitcher mice, to test different experimental therapies resulting in developments that have led to progressive improvements in the therapeutic impact. Some recent advances have been in the areas of gene therapy and substrate reduction therapy (SRT), as well as using these in combination with HSCT. Unfortunately, new experimental approaches have encountered obstacles which have impeded the translation of novel therapies to human patients. In an effort to identify a safe adjunct therapy, D-cycloserine was tested in preliminary studies in twitcher mice. When administered as a standalone therapy, D-cycloserine was shown to lengthen the lifespan of twitcher mice in a small but significant manner. D-Cycloserine is an FDA approved antibiotic used for drug resistant tuberculosis. It also acts as a partial agonist of the NMDA receptor, which has led to numerous human studies for a range of neuropsychiatric and neurological conditions. In addition, D-cycloserine may inhibit serine palmitoyltransferase (SPT), which catalyzes the rate-limiting step in sphingolipid production. The enantiomer, L-cycloserine, is a much more potent inhibitor of SPT than D-cycloserine. Previously, L-cycloserine was found to act as an effective SRT agent in twitcher mice as both a standalone therapy and as part of combination therapies. L-Cycloserine is not approved for human use, and its potent inhibitory properties may limit its ability to maintain a level of partial inactivation of SPT that is also safe. In theory, D-cycloserine would encompass a much broader dosage range to achieve a safe degree of partial inhibition of SPT, which increases the likelihood it could advance to human studies in patients with Krabbe disease. Furthermore, additional properties of D-cycloserine raise the possibility of other therapeutic mechanisms that could be exploited for the treatment of this disease.

The habenula and iron metabolism in cerebral mouse models of multiple sclerosis.

Iron accumulates in the CNS of patients with multiple sclerosis, but our understanding of the mechanism accounting for this accumulation is unclear. Mouse models of cerebral experimental autoimmune encephalomyelitis (EAE) in C57BL/6 and SJL mice were used together with a histochemical stain for iron and immunohistochemical stains for transferrin receptor, synaptophysin, iron regulatory protein 1 (IRP1) and/or IRP2 to investigate the role of disease activity on CNS iron metabolism. The expression of transferrin receptor, but not IRP1 or IRP2, increased in the medial habenula, which is adjacent to the third ventricle, in response to both types of cerebral EAE. In the habenula, the elevated expression of transferrin receptor in C57BL/6 mice with cerebral EAE was generally restricted to the medial habenula while the expression in SJL mice with cerebral EAE was more diffusely expressed. Iron levels were increased in all regions of the habenula in C57BL/6 mice with cerebral EAE, and in the medial and medial lateral but not the lateral habenula in SJL mice with cerebral EAE. Synaptophysin, which has been observed previously in endocytic vesicles together with the transferrin receptor, was concentrated at the medial habenula, but its levels did not increase with disease in C57BL/6 mice with cerebral EAE. Our results support the model that the medial habenula responds to disease activity by upregulating transferrin receptor to facilitate the movement of iron into the brain from the third ventricle, raising the possibility that a similar mechanism accounts for iron accumulation in deep gray matter structures in patients with multiple sclerosis.

The effect of omeprazole on the development of experimental autoimmune encephalomyelitis in C57BL/6J and SJL/J mice.

BACKGROUND: Gastric disturbances such as dyspepsia are routinely encountered by multiple sclerosis (MS) patients, and these conditions are often treated with gastric acid suppressors such as proton pump inhibitors, histamine H2 receptor antagonists, or antacids. The proton pump inhibitor omeprazole can alter the gut flora and immune responses, both of which can influence the course of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The objective of the current study was to examine the effect of omeprazole treatment on the development of EAE. Bacterial microbiome analysis of mouse fecal pellets was determined in C57BL/6J EAE mice chronically treated with omeprazole, and spleen immune cell content, clinical scores, weight, rotarod latency, and histopathology were used as outcome measures in C57BL/6J and SJL/J mice with EAE. RESULTS: Omeprazole treatment resulted in decreases in Akkermansia muciniphila and Coprococcus sp. and an increase in unidentified bacteria in the family S24-7 (order Bacteroidales) in C57BL/6J mice with EAE. Omeprazole did not alter spleen immune cell content compared to vehicle in EAE mice, but differences independent of treatment were observed in subsets of T cells between early and advanced disease in C57BL/6J mice as well as between the two strains of mice at an advanced disease stage. Omeprazole caused no difference in clinical scores in either strain, but significantly lowered weight gain compared to vehicle in the C57BL/6J mice with EAE. Omeprazole also did not alter rotarod behavior or hindbrain inflammatory cell infiltration compared to vehicle in both strains of mice with EAE. Rotarod latency did reveal a negative correlation with clinical scores during active disease in both mouse strains, but not during clinical remission in SJL/J mice, suggesting that rotarod can detect disability not reflected in the clinical scores. CONCLUSIONS: Despite alterations in the gut microbiota and weight gain in the C57BL/6J EAE model, omeprazole had no effect on multiple measures of disease activity in C57BL/6J and SJL/J mice with EAE, supporting the notion that omeprazole does not substantially influence disease activity in MS patients.