title: Diagnostic and therapeutic potential of tetanus toxin-derivatives in neurological diseases.
abstract: We assessed the ex vivo reactivity of peptidic constructs of Tet1 (analog of tetanus toxin non-virulent C fragment) with sequence homology to the cysteine-active site of thioredoxin (Tet1THO) or tetralysine (Tet1PLYS) with oxidative species or axonopathic sodium cyanate (NaOCN), respectively. We then assessed their neuronal uptake in vivo in laboratory animals. The reactivity of Tet1PLYS with NaOCN (1:2.5 to 1:37.5 molar ratios) or Tet1THO with hydrogen peroxide (1:0.4 to 1:6.2 molar ratios) was assessed by mass spectrometry. Green fluorescence protein (GFP)-tagged Tet1-derivatives (3 mg/ml in artificial cerebrospinal fluid) were administered daily to rats by intramuscular injection in latissimus dorsi at lumborum at the dose of 1 μl/g of body weight, for 3 days. Motor neuron uptake was assessed after double immunolabeling for GFP and choline acetyltransferase. Mass spectrometry analysis successfully demonstrated the ex vivo reactivity of Tet1-derivatives in a concentration-dependent manner. Confocal microscopy revealed the localization of Tet1-derivatives in axons and motor neuron cell bodies. Intramuscular delivery of Tet1-derivatives appears to be a practical approach to circumvent the blood nerve barrier and selectively deliver small molecules to the nervous system, for diagnostic and/or treatment purposes.
authors.affiliation: Center for Research on Occupational & Environmental Toxicology, Oregon Health & Science University (OHSU), 3181 Sam Jackson Park Road, mail code L606, Portland, OR, 97239, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kassa
authors.forename: V
authors.initials: V
authors.lastname: Monterroso
authors.forename: L L
authors.initials: LL
authors.lastname: David
authors.forename: D
authors.initials: D
authors.lastname: Tshala-Katumbay
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D007273:Injections, Intramuscular; D008297:Male; D009046:Motor Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D010446:Peptide Fragments / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017385:Sequence Homology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects; D013744:Tetanus Toxin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013879:Thioredoxins / Q000737:chemistry
chemical_list: D009498:Neurotoxins; D010446:Peptide Fragments; D013744:Tetanus Toxin; D013879:Thioredoxins