Prion deposition in olfactory biopsy of sporadic Creutzfeldt-Jakob disease

Currently, definite peripheral markers for the in vivo diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) are not available. Here, we report the presence of pathological prion protein in the olfactory mucosa of a case with sporadic Creutzfeldt-Jakob disease. Prion protein immunoreactivity was detected in an olfactory biopsy performed 45 days after the disease onset, suggesting that the involvement of olfactory epithelium is an early event in sporadic Creutzfeldt-Jakob disease.     

Constitutive and induced neurogenesis in the adult mammalian brain: manipulation of endogenous precursors toward CNS repair

Over most of the past century of modern neuroscience, it was thought that the adult brain was completely incapable of generating new neurons. During the past 3 decades, research exploring potential neuronal replacement therapies has focused on replacing lost neurons by transplanting cells or grafting tissue into diseased regions of the brain. However, in the last decade, the development of new techniques has resulted in an explosion of new research showing that neurogenesis, the birth of new neurons, normally occurs in two limited and specific regions of the adult mammalian brain and that there are significant numbers of multipotent neural precursors in many parts of the adult mammalian brain. Recent advances in our understanding of related events of neural development and plasticity, including the role of radial glia in developmental neurogenesis and the ability of endogenous precursors present in the adult brain to be induced to produce neurons and partially repopulate brain regions affected by neurodegenerative processes, have led to fundamental changes in the views about how the brain develops as well as to approaches by which endogenous precursors might be recruited to repair the adult brain. Recruitment of new neurons can be induced in a region-specific, layer-specific and neuronal-type-specific manner, and, in some cases, newly recruited neurons can form long-distance connections to appropriate targets. Elucidation of the relevant molecular controls may both allow control over transplanted precursor cells and potentially allow the development of neuronal replacement therapies for neurodegenerative disease and other CNS injuries that do not require transplantation of exogenous cells.     

Lymphoblastoid cell lines of Rett syndrome patients exposed to oxidative-stress-induced apoptosis

Despite the identification of mutations in the methyl CpG binding protein 2 gene, the pathogenesis of Rett syndrome (RS) is still unknown. In order to clarify the role of apoptosis in this disorder, we studied lymphoblastoid cell lines in five classical RS patients and five controls, incubated with 2-deoxy-d-ribose (dRib), a reducing sugar that induces apoptosis in human cells, through oxidative damage. The apoptotic response was detected by flow cytometric analysis and agarose gel electrophoresis. The cells of RS patients showed a lower percentage of apoptosis in a routine condition than those of controls did, whereas, in the presence of dRib, the percentage of apoptotic cells in RS patients increased with time and reached the same percentage of those of controls at 72 h. The data observed here suggest that RS may have a low susceptibility or an increased resistance to the apoptotic cell death, which may be corrected only in the presence of a strong apoptotic stimulus.     

Nasu-Hakola disease: a rare entity in Italy. Critical review of the literature

Nasu-Hakola disease (NHD, polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL) is a recessively inherited disorder characterized by systemic bone cysts and progressive presenile dementia associated with sclerosing encephalopathy. The disease has a worldwide distribution, but most patients have been reported in Finland and in Japan; in Italy there are anecdotal reports. The combination of neuropsychiatric symptoms and bone cysts is unique to this disease, which we believe to be underestimated in Italy. The molecular defect has been identified in loss-of-function mutations in the TYROBP gene in Finnish and in Japanese patients, and in the TREM2 gene in other families of different ethnic origins. We reviewed the international literature to define better the diagnostic steps and to draw the attention of neurologists and orthopaedic specialists to the disease. The identification of new cases followed by appropriate genetic counselling, genetic analysis, and study of the territorial distribution of affected patients could be a good strategy to follow in order to improve understanding of the disease.     

New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse

The antimyotonic activity of chiral derivatives of mexiletine and tocainide, selected as potent use-dependent blockers of skeletal muscle sodium channels, was evaluated in vivo acutely in myotonic ADR mice. The compounds had either aromatic (Me4 and Me6) or branched isopropyl groups (Me5 and To1) on the asymmetric centre, or had this latter one methylene apart from the amino group (Me2). Therapeutic doses of mexiletine (5-10 mg/kg) and tocainide (7-20 mg/kg) significantly reduced the long time of righting reflex (TRR), typical of ADR mice. Me4, Me5 and Me6 were 2-fold more potent than mexiletine. To1 fully normalised the TRR at 7 mg/kg. The electromyographic analysis confirmed a muscle-based activity for drug effectiveness on TRR. All the compounds reduced the myotonic hyperexcitability of intercostal muscle fibres when tested in vitro by current-clamp recordings, with a potency correlated with their action on sodium channels. On stimulus-evoked firing, the isopropyl analogues were 2-4-fold more potent than parent compounds, while the aromatic analogues were about 10-fold more potent than mexiletine. Patch-clamp recordings confirmed a normal-like pharmacological sensitivity of sodium channels of native ADR muscle fibres. Finally, the in vivo antimyotonic activity is due to the block of sodium channels and divergences with in vitro potency can be related to structure-based changes in drug pharmacokinetics.     

Plasma antioxidant status, immunoglobulin g oxidation and lipid peroxidation in demented patients: relevance to Alzheimer disease and vascular dementia

A large body of evidence supports a role of oxidative stress in Alzheimer disease (AD) and in cerebrovascular disease. A vascular component might be critical in the pathophysiology of AD, but there is a substantial lack of data regarding the simultaneous behavior of peripheral antioxidants and biomarkers of oxidative stress in AD and vascular dementia (VaD). Sixty-three AD patients, 23 VaD patients and 55 controls were included in the study. We measured plasma levels of water-soluble (vitamin C and uric acid) and lipophilic (vitamin E, vitamin A, carotenoids including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) antioxidant micronutrients as well as levels of biomarkers of lipid peroxidation [malondialdehyde (MDA)] and of protein oxidation [immunoglobulin G (IgG) levels of protein carbonyls and dityrosine] in patients and controls. With the exception of beta-carotene, all antioxidants were lower in demented patients as compared to controls. Furthermore, AD patients showed a significantly higher IgG dityrosine content as compared to controls. AD and VaD patients showed similar plasma levels of plasma antioxidants and MDA as well as a similar IgG content of protein carbonyls and dityrosine. We conclude that, independent of its nature-vascular or degenerative-dementia is associated with the depletion of a large spectrum of antioxidant micronutrients and with increased protein oxidative modification. This might be relevant to the pathophysiology of dementing disorders, particularly in light of the recently suggested importance of the vascular component in AD development.     

Nerve growth factor and chronic daily headache: a potential implication for therapy

The pivotal role of nerve growth factor in inducing hyperalgesia and central sensitization has been emphasized in experimental pain models. Higher nerve growth factor levels have recently been found in the cerebrospinal fluid of patients with chronic daily headache. These levels were significantly correlated with the cerebrospinal fluid levels of substance P and calcitonin gene-related peptide, supporting the involvement of this neurotrophin in enhancing the production of the two sensory neuropeptides of the trigemino-vascular system in chronic daily headache. This may, in part, account for the long-lasting sensitization and activation of this system, which could contribute to headache chronicity. More recent research has shown a significant correlation between the higher cerebrospinal fluid levels of nerve growth factor and those of another neurotrophin, the brain-derived neurotrophic factor, as well as glutamate in chronic daily headache patients. These findings suggest the potential involvement of nerve growth factor-mediated upregulation of brain-derived neurotrophic factor in persistent head pain. Therefore, nerve growth factor appears to indirectly exert its effect through enhancing glutamatergic transmission involved in the processing of head pain via brain-derived neurotrophic factor. Based on these data, a potential application can be hypothesized for novel strategies targeting neurotrophins (nerve growth factor and brain-derived neurotrophic factor) and their receptors to chronic daily headache. To date, the majority of the molecules discovered in this regard have been scarcely or never proved in animal pain models and are far from clinical use in chronic pain, including chronic daily headache. If this approach is to be developed in the near future, research should be focused on identifying strategies with few central side effects and specific selective action on central sites involved in chronic head pain and more generally in chronic pain conditions. This will represent a very difficult challenge, taking into account the pleiotropic effect of nerve growth factor and the wide range of intracellular signalling pathways activated by this neurotrophin which are not limited to the nociceptive system.