Fragment C Domain of Tetanus Toxin Mitigates Methamphetamine Neurotoxicity and Its Motor Consequences in Mice
Mendieta, Liliana (Instituto Cajal (Consejo Superior de Investigaciones Científicas))
Granado, Noelia (Instituto Cajal (Consejo Superior de Investigaciones Científicas))
Aguilera, José (Universitat Autònoma de Barcelona. Institut de Neurociències)
Tizabi, Yousef (Instituto Cajal (Consejo Superior de Investigaciones Científicas))
Moratalla, Rosario (Instituto Cajal (Consejo Superior de Investigaciones Científicas))
Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular

Fecha:	2016
Resumen:	The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a nontoxic peptide with demonstrated in vitro and in vivo neuroprotective effects against striatal dopaminergic damage induced by 1-methyl-4-phenylpyridinium and 6-hydoxydopamine, suggesting its possible therapeutic potential in Parkinson's disease. Methamphetamine, a widely abused psychostimulant, has selective dopaminergic neurotoxicity in rodents, monkeys, and humans. This study was undertaken to determine whether Hc-TeTx might also protect against methamphetamine-induced dopaminergic neurotoxicity and the consequent motor impairment. For this purpose, we treated mice with a toxic regimen of methamphetamine (4mg/kg, 3 consecutive i. p. injections, 3 hours apart) followed by 3 injections of 40 ug/kg of Hc-TeTx into grastrocnemius muscle at 1, 24, and 48 hours post methamphetamine treatment. We found that Hc-TeTx significantly reduced the loss of dopaminergic markers tyrosine hydroxylase and dopamine transporter and the increases in silver staining (a well stablished degeneration marker) induced by methamphetamine in the striatum. Moreover, Hc-TeTx prevented the increase of neuronal nitric oxide synthase but did not affect microglia activation induced by methamphetamine. Stereological neuronal count in the substantia nigra indicated loss of tyrosine hydroxylase-positive neurons after methamphetamine that was partially prevented by Hc-TeTx. Importantly, impairment in motor behaviors post methamphetamine treatment were significantly reduced by Hc-TeTx. Here we demonstrate that Hc-TeTx can provide significant protection against acute methamphetamine-induced neurotoxicity and motor impairment, suggesting its therapeutic potential in methamphetamine abusers.
Ayudas:	Ministerio de Economía y Competitividad SAF2013-48532-R
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Fragment C tetanus toxin ; Methamphetamine ; Neuroprotection ; Neurotoxicity ; Neuroinflammation
Publicado en:	International journal of neuropsychopharmacology, Vol. 19 (march 2016) , ISSN 1469-5111

DOI: 10.1093/ijnp/pyw021
PMID: 26945022

11 p, 14.5 MB

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