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Pha1ß is a neurotoxin from the venom of the Phoneutria nigriventer spider, available as CTK 01512-2, a recombinant peptide. Owing to its antinociceptive and analgesic properties, CTK 01512-2 has been described to alleviate neuroinflammatory responses. Despite the diverse actions of CTK 01512-2 on the nervous system, little is known regarding its neuroprotective effect, especially in neurodegenerative conditions such as Huntington's disease (HD), a genetic movement disorder without cure. Here, we investigated whether CTK 01512-2 has a neuroprotective effect in a mouse model of HD. We hypothesized that spinal cord neurons might represent a therapeutic target, because the spinal cord seems to be involved in the motor symptoms ofHD(BACHD)mice. We treated BACHDmice with CTK 01512-2 by intrathecal injection and performed in vivo motor behavioural and morphological analyses in the CNS (brain and spinal cord) and muscles. Our data showed that intrathecal injection of CTK 01512-2 significantly improved motor performance in the open field task. CTK 01512-2 protected neurons in the spinal cord (but not in the brain) from death, suggesting a local effect. CTK 01512-2 exerted its neuroprotective effect by inhibiting BACHD neuronal apoptosis, as revealed by a reduction in caspase-3 in the spinal cord. CTK 01512-2 was also able to revert BACHD muscle atrophy. In conclusion, our data suggest a novel role for CTK 01512-2 acting directly in the spinal cord to ameliorate morphofunctional aspects of spinal cord neurons and muscles and improve the performance of BACHD mice in motor behavioural tests. Given that HD shares similar symptoms with many neurodegenerative conditions, the findings presented herein might also be applicable to other disorders. [ABSTRACT FROM AUTHOR]

• First report of antileishmanial activity of fullerol. • Fullerol reduces hepatic parasite load in murine model of visceral leishmaniasis. • Liposome encapsulation of fullerol enhances its antileishmanial activity in vivo. • An innovative therapeutic approach based on the association of two nanosystems. Visceral leishmaniasis (VL) is a systemic parasitic disease that leads to high rates of morbidity and mortality in humans worldwide. There is a great need to develop new drugs and novel strategies to make chemotherapy for this disease more efficacious and well tolerated. Recent reports on the immunomodulatory effects and the low toxicity of the spherical carbon nanostructure fullerol led us to investigate in vitro and in vivo antileishmanial activity in free and encapsulated forms in liposomes. When assayed against intramacrophagic Leishmania amastigotes, fullerol showed a dose-dependent reduction of the infection index with IC 50 of 0.042 mg/mL. When given daily by i.p. route for 20 days (0.05 mg/kg/d) in a murine model of acute VL, fullerol promoted significant reduction in the liver parasite load. To improve the delivery of fullerol to the infection sites, liposomal formulations were prepared by the dehydration-rehydration method. When evaluated in the acute VL model, liposomal fullerol (Lip-Ful) formulations given i.p. at 0.05 and 0.2 mg/kg with 4-days intervals were more effective than the free form, with significant parasite reductions in both liver and spleen. Lip-Ful at 0.2 mg/kg promoted complete parasite elimination in the liver. The antileishmanial activity of Lip-Ful was further confirmed in a chronic model of VL. Lip-Ful was also found to induce secretion of pro-inflammatory TNF-α, IFN-γ and IL-1β cytokines. In conclusion, this work reports for the first time the antileishmanial activity of fullerol and introduces an innovative approach for treatment of VL based on the association of this nanostructure with liposomes. [ABSTRACT FROM AUTHOR]

Abstract: Recent work has provided compelling evidence that increased levels of acetylcholine (ACh) can be protective in heart failure, whereas reduced levels of ACh secretion can cause heart malfunction. Previous data show that cardiomyocytes themselves can actively secrete ACh, raising the question of whether this cardiomyocyte derived ACh may contribute to the protective effects of ACh in the heart. To address the functionality of this non-neuronal ACh machinery, we used cholinesterase inhibitors and a siRNA targeted to AChE (acetylcholinesterase) as a way to increase the availability of ACh secreted by cardiac cells. By using nitric oxide (NO) formation as a biological sensor for released ACh, we showed that cholinesterase inhibition increased NO levels in freshly isolated ventricular myocytes and that this effect was prevented by atropine, a muscarinic receptor antagonist, and by inhibition of ACh synthesis or vesicular storage. Functionally, cholinesterase inhibition prevented the hypertrophic effect as well as molecular changes and calcium transient alterations induced by adrenergic overstimulation in cardiomyocytes. Moreover, inhibition of ACh storage or atropine blunted the anti-hypertrophic action of cholinesterase inhibition. Altogether, our results show that cardiomyocytes possess functional cholinergic machinery that offsets deleterious effects of hyperadrenergic stimulation. In addition, we show that adrenergic stimulation upregulates expression levels of cholinergic components. We propose that this cardiomyocyte cholinergic signaling could amplify the protective effects of the parasympathetic nervous system in the heart and may counteract or partially neutralize hypertrophic adrenergic effects. [Copyright &y& Elsevier]

Abstract: Recent work has provided compelling evidence that increased levels of acetylcholine (ACh) can be protective in heart failure, whereas reduced levels of ACh secretion can cause heart malfunction. Previous data show that cardiomyocytes themselves can actively secrete ACh, raising the question of whether this cardiomyocyte derived ACh may contribute to the protective effects of ACh in the heart. To address the functionality of this non-neuronal ACh machinery, we used cholinesterase inhibitors and a siRNA targeted to AChE (acetylcholinesterase) as a way to increase the availability of ACh secreted by cardiac cells. By using nitric oxide (NO) formation as a biological sensor for released ACh, we showed that cholinesterase inhibition increased NO levels in freshly isolated ventricular myocytes and that this effect was prevented by atropine, a muscarinic receptor antagonist, and by inhibition of ACh synthesis or vesicular storage. Functionally, cholinesterase inhibition prevented the hypertrophic effect as well as molecular changes and calcium transient alterations induced by adrenergic overstimulation in cardiomyocytes. Moreover, inhibition of ACh storage or atropine blunted the anti-hypertrophic action of cholinesterase inhibition. Altogether, our results show that cardiomyocytes possess functional cholinergic machinery that offsets deleterious effects of hyperadrenergic stimulation. In addition, we show that adrenergic stimulation upregulates expression levels of cholinergic components. We propose that this cardiomyocyte cholinergic signaling could amplify the protective effects of the parasympathetic nervous system in the heart and may counteract or partially neutralize hypertrophic adrenergic effects. [Copyright &y& Elsevier]