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Notartomaso S.,I.R.C.C.S. Neuromed | Zappulla C.,I.R.C.C.S. Neuromed | Biagioni F.,I.R.C.C.S. Neuromed | Cannella M.,I.R.C.C.S. Neuromed | And 14 more authors.
Molecular Brain | Year: 2013

Background: Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1. Results: Symptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells. Conclusions: These data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel "cerebellum-specific", effective, and safe symptomatic drugs for the treatment of SCA1 in humans. © 2013 Notartomaso et al.; licensee BioMed Central Ltd.

Pompili M.,Mental Health and Sensory Organs | Pompili M.,Harvard University | Serafini G.,Mental Health and Sensory Organs | Innamorati M.,European University at Rome | And 4 more authors.
Schizophrenia Research | Year: 2011

Many studies have confirmed that the risk of suicide in patients with first-episode psychosis (FEP) is high, and high rates of premature mortality, particularly from suicide, may occur in the early phases of schizophrenia. However, suicide rates are difficult to measure in FEP patients, even in carefully defined samples, and there is relatively little specific information about the risk of suicide at illness onset or retrospectively concerning the untreated psychotic period. This selected review of the literature investigates suicidal behaviour with particular regard to severe suicidality (plans and attempts) and risk factors associated with suicide in FEP patients. A search was performed to identify all papers and book chapters during the period 1965-2010, and approximately 100 studies met the inclusion criteria. Most of evidence suggests that risk of suicidal behaviour is relatively high in FEP patients. The research reports highlight the need for universal, comprehensive, public mental health interventions aimed, not only toward early detection, but also toward the rapid engagement in treatment of people with psychoses. These interventions should include an adequate assessment of suicidal behaviour in patients with FEP, and an examination of the efficacy of specific components of the interventions. © 2011 Elsevier B.V.

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