Long-lasting efficacy of the cognitive enhancer Cytotoxic Necrotizing Factor 1

Borrelli, Sonia; Musilli, Marco; Martino, Assunta; Diana, Giovanni

doi:10.1016/j.neuropharm.2012.05.031

Cited by 16 publications

(12 citation statements)

References 58 publications

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“…Reversing this feature by modulation of Rho GTPases might be of therapeutic value (Bongmba et al, 2011). This effect, together with those previously described on learning ability (Diana et al, 2007; De Viti et al, 2010; De Filippis et al, 2012; Borrelli et al, 2013), candidates Rho GTPase modulators as a new avenue for the treatment of several disorders of the central nervous system (Musilli et al, 2013). …”

Section: Discussionsupporting

confidence: 52%

Rho GTPase-dependent plasticity of dendritic spines in the adult brain

Martino

Ettorre

Musilli

et al. 2013

Front. Cell. Neurosci.

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Brain activity is associated with structural changes in the neural connections. However, in vivo imaging of the outer cortical layers has shown that dendritic spines, on which most excitatory synapses insist, are predominantly stable in adulthood. Changes in dendritic spines are governed by small GTPases of the Rho family through modulation of the actin cytoskeleton. Yet, while there are abundant data about this functional effect of Rho GTPases in vitro, there is limited evidence that Rho GTPase signaling in the brain is associated with changes in neuronal morphology. In the present work, both chronic in vivo two-photon imaging and Golgi staining reveal that the activation of Rho GTPases in the adult mouse brain is associated with little change of dendritic spines in the apical dendrites of primary visual cortex pyramidal neurons. On the contrary, considerable increase in spine density is observed (i) in the basal dendrites of the same neurons (ii) in both basal and apical dendrites of the hippocampal CA1 pyramidal cells. While confirming that Rho GTPase-dependent increase in spine density can be substantial, the study indicates region and dendrite selectivity with relative stability of superficial cortical circuits.

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Section: Discussionsupporting

confidence: 52%

Rho GTPase-dependent plasticity of dendritic spines in the adult brain

Martino

Ettorre

Musilli

et al. 2013

Front. Cell. Neurosci.

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“…Local injection of CNF1 has been shown to increase dendritic spine density in the rat visual cortex [41]. More importantly, these newly formed dendritic spines appear to be functional, as intracerebroventricular (ICV) injection of CNF1 can persistently (up to 90 days post-treatment) increase hippocampal neurotransmission, long-term potentiation (LTP), and memory in wild-type mice [42][43][44]. These benefits may also translate to other neurological disorders.…”

Section: Direct Modulation Of Rho-gtpases For Ad Treatmentmentioning

confidence: 99%

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

Lefort

2015

Neurotherapeutics

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Alzheimer's disease (AD) is a monumental public health crisis with no effective cure or treatment. To date, therapeutic strategies have focused almost exclusively on upstream signaling events in the disease, namely on β-amyloid and amyloid precursor protein processing, and have, unfortunately, yielded few, if any, promising results. An alternative approach may be to target signaling events downstream of β-amyloid and even tau. However, with so many pathways already linked to the disease, understanding which ones are "drivers" versus "passengers" in the pathogenesis of the disease remains a tremendous challenge. Given the critical roles of Rho-guanosine triphosphatases (GTPases) in regulating the actin cytoskeleton and spine dynamics, and the strong association between spine abnormalities and cognition, it is not surprising that mutations in a number of genes involved in RhoGTPase signaling have been implicated in several brain disorders, including schizophrenia and autism. And now, there is mounting literature implicating Rho-GTPase signaling in AD pathogenesis as well. Here, I review this evidence, with a particular emphasis on the regulators of Rho-GTPase signaling, namely guanine nucleotide exchange factors and GTPaseactivating proteins. Several of these have been linked to various aspects of AD, and each offers a novel potential therapeutic target for AD.

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“…Several reports have demonstrated the first proofs of concept that bacterial toxins activating Rho GTPases are endowed with the ability to treat or prevent cognitive and infectious diseases. For example, a series of studies now report that the injection of CNF1 into the brain has a positive impact on the development and differentiation of astrocytes, a phenomenon that likely underlies the cognition-enhancing properties of the toxin [92,93]. The link between Rho GTPases and innate immunity has been established through the discovery of a dominant negative mutation of Rac2 D57N in a patient with a neutrophil immunodeficiency syndrome [94].…”

Section: Translational Research Exploiting Rho Signalingmentioning

confidence: 99%