title: Fragment C Domain of Tetanus Toxin Mitigates Methamphetamine Neurotoxicity and Its Motor Consequences in Mice.
abstract: 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.
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid, Spain (Drs Mendieta, Granado, and Moratalla); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain (Drs Mendieta, Granado, Aguilera, and Moratalla); Institut de Neurociències and Departament de Bioquímica i de Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain (Dr Aguilera); Departament of Pharmacology, Howard University College of Medicine, Washington, DC (Dr Tizabi).
authors.forename: Liliana
authors.initials: L
authors.lastname: Mendieta
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid, Spain (Drs Mendieta, Granado, and Moratalla); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain (Drs Mendieta, Granado, Aguilera, and Moratalla); Institut de Neurociències and Departament de Bioquímica i de Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain (Dr Aguilera); Departament of Pharmacology, Howard University College of Medicine, Washington, DC (Dr Tizabi).
authors.forename: Noelia
authors.initials: N
authors.lastname: Granado
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid, Spain (Drs Mendieta, Granado, and Moratalla); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain (Drs Mendieta, Granado, Aguilera, and Moratalla); Institut de Neurociències and Departament de Bioquímica i de Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain (Dr Aguilera); Departament of Pharmacology, Howard University College of Medicine, Washington, DC (Dr Tizabi).
authors.forename: José
authors.initials: J
authors.lastname: Aguilera
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid, Spain (Drs Mendieta, Granado, and Moratalla); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain (Drs Mendieta, Granado, Aguilera, and Moratalla); Institut de Neurociències and Departament de Bioquímica i de Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain (Dr Aguilera); Departament of Pharmacology, Howard University College of Medicine, Washington, DC (Dr Tizabi).
authors.forename: Yousef
authors.initials: Y
authors.lastname: Tizabi
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Madrid, Spain (Drs Mendieta, Granado, and Moratalla); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain (Drs Mendieta, Granado, Aguilera, and Moratalla); Institut de Neurociències and Departament de Bioquímica i de Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain (Dr Aguilera); Departament of Pharmacology, Howard University College of Medicine, Washington, DC (Dr Tizabi). moratalla@cajal.csic.es.
authors.forename: Rosario
authors.initials: R
authors.lastname: Moratalla
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002452:Cell Count; D003342:Corpus Striatum / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D010446:Peptide Fragments / Q000494:pharmacology*; D045442:Rotarod Performance Test; D013744:Tetanus Toxin / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D010446:Peptide Fragments; D013744:Tetanus Toxin; C040635:tetanus toxin fragment C; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase
keywords: fragment C tetanus toxin; methamphetamine; neuroinflammation; neuroprotection; neurotoxicity