Protective effects of polysialic acids (PSAs) and its mimics on the nervous system after injury

Polysialic acid (PSA), a polymer of alpha-2,8 linked sialic acid residues, is a negatively charged macromolecular glycan mainly attached to neural cell adhesion molecules (NCAM). Studies have shown that PSA is not only essential for the development of normal brain circulation, but also for synaptic plasticity, learning and memory in adults. Although the occurrence, features, biosynthesis, and physiological roles of PSA and related effects on related diseases, including schizophrenia, bipolar disorder, neurodegenerative diseases and cancer, have been well reviewed, the important roles of PSA and its mimics in the regeneration of the nervous system following injury have not been well discussed. As a consequence, this article comprehensively reviews the effects of small organic compounds that simulate PSA, such as tegaserod and 5-nonyloxytryptamine (5-NOT), on the nervous system of mammals, suggesting that these mimetics may have tremendous therapeutic potential, especially for strategies aimed at tissue repair after injury of the nervous system.

Overview of the Neuroprotective Effects of the MAO-Inhibiting Antidepressant Phenelzine

Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite β-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N-acetylamino acids.

Exploratory proteomic analysis implicates the alternative complement cascade in primary CNS vasculitis

ObjectiveTo identify molecular correlates of primary angiitis of the CNS (PACNS) through proteomic analysis of CSF from a biopsy-proven patient cohort.MethodsUsing mass spectrometry, we quantitatively compared the CSF proteome of patients with biopsy-proven PACNS (n = 8) to CSF from individuals with noninflammatory conditions (n = 11). Significantly enriched molecular pathways were identified with a gene ontology workflow, and high confidence hits within enriched pathways (fold change >1.5 and concordant Benjamini-Hochberg–adjusted p < 0.05 on DeSeq and t test) were identified as differentially regulated proteins.ResultsCompared to noninflammatory controls, 283 proteins were differentially expressed in the CSF of patients with PACNS, with significant enrichment of the complement cascade pathway (C4-binding protein, CD55, CD59, properdin, complement C5, complement C8, and complement C9) and neural cell adhesion molecules. A subset of clinically relevant findings were validated by Western blot and commercial ELISA.ConclusionsIn this exploratory study, we found evidence of deregulation of the alternative complement cascade in CSF from biopsy-proven PACNS compared to noninflammatory controls. More specifically, several regulators of the C3 and C5 convertases and components of the terminal cascade were significantly altered. These preliminary findings shed light on a previously unappreciated similarity between PACNS and systemic vasculitides, especially anti-neutrophil cytoplasmic antibody–associated vasculitis. The therapeutic implications of this common biology and the diagnostic and therapeutic utility of individual proteomic findings warrant validation in larger cohorts.

Cross-generational impact of a male murine pheromone 2-sec-butyl-4,5-dihydrothiazole in female mice

The current understanding of the activity of mammalian pheromones is that endocrine and behavioural effects are limited to the exposed individuals. Here, we demonstrate that the nasal exposure of female mice to a male murine pheromone stimulates expansion of mammary glands, leading to prolonged nursing of pups. Subsequent behavioural testing of the pups from pheromone-exposed dams exhibited enhanced learning. Sialic acid components in the milk are known to be involved in brain development. We hypothesized that the offspring might have received more of this key nutrient that promotes brain development. The mRNA for polysialyltransferase, which produces polysialylated neural cell adhesion molecules related to brain development, was increased in the brain of offspring of pheromone-exposed dams at post-natal day 10, while it was not different at embryonic stages, indicating possible differential brain development during early post-natal life.