Beneficial Effects of the Calcium Channel Blocker CTK 01512-2 in a Mouse Model of Multiple Sclerosis

  • Mol Neurobiol. 2018 Dec;55(12):9307-9327. doi: 10.1007/s12035-018-1049-1.
Rodrigo B M Silva  1  2 ,  Samuel Greggio  3  4 ,  Gianina T Venturin  3 ,  Jaderson C da Costa  3 ,  Marcus V Gomez  5 ,  Maria M Campos  6  7  8  9
Affiliations
  • 1. Escola de Medicina, Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, 90619-900, Brazil.
  • 2. Escola de Ciências da Saúde, Centro de Toxicologia e Farmacologia, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, Porto Alegre, RS, 90619-900, Brazil.
  • 3. Centro de Pesquisa Pré-Clínica, Instituto do Cérebro do Rio Grande do Sul - Brain Institute (BraIns), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, 90610-000, Brazil.
  • 4. Escola de Ciências da Saúde, Curso de Graduação em Biomedicina, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, 90619-900, Brazil.
  • 5. Núcleo de Pós-Graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, 30150-240, Brazil.
  • 6. Escola de Medicina, Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, 90619-900, Brazil. [email protected].
  • 7. Escola de Ciências da Saúde, Centro de Toxicologia e Farmacologia, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, Porto Alegre, RS, 90619-900, Brazil. [email protected].
  • 8. Escola de Ciências da Saúde, Curso de Graduação em Odontologia, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, 90619-900, Brazil. [email protected].
  • 9. Escola de Ciências da Saúde, Programa de Pós-Graduação em Odontologia, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, 90619-900, Brazil. [email protected].
PMID: 29667130 DOI: 10.1007/s12035-018-1049-1
Abstract

Voltage-gated calcium channels (VGCCs) play a critical role in neuroinflammatory diseases, such as multiple sclerosis (MS). CTK 01512-2 is a recombinant version of the peptide Phα1β derived from the spider Phoneutria nigriventer, which inhibits N-type VGCC/TRPA1-mediated calcium influx. We investigated the effects of this molecule in the mouse model of experimental autoimmune encephalomyelitis (EAE). The effects of CTK 01512-2 were compared to those displayed by ziconotide-a selective N-type VGCC blocker clinically used for chronic pain-and fingolimod-a drug employed for MS treatment. The intrathecal (i.t.) treatment with CTK 01512-2 displayed beneficial effects, by preventing nociception, body weight loss, splenomegaly, MS-like clinical and neurological scores, impaired motor coordination, and memory deficits, with an efficacy comparable to that observed for ziconotide and fingolimod. This molecule displayed a favorable profile on EAE-induced neuroinflammatory changes, including inflammatory infiltrate, demyelination, pro-inflammatory cytokine production, glial activation, and glucose metabolism in the brain and spinal cord. The recovery of spatial memory, besides a reduction of serum Leptin levels, allied to central and peripheral elevation of the anti-inflammatory cytokine IL-10, was solely modulated by CTK 01512-2, dosed intrathecally. The intravenous (i.v.) administration of CTK 01512-2 also reduced the EAE-elicited MS-like symptoms, similarly to that seen in Animals that received fingolimod orally. Ziconotide lacked any significant effect when dosed by i.v. route. Our results indicate that CTK 01512-2 greatly improved the neuroinflammatory responses in a mouse model of MS, with a higher efficacy when compared to ziconotide, pointing out this molecule as a promising Adjuvant for MS management.

Keywords
CTK 01512-2; Calcium signaling; Fingolimod; Multiple sclerosis; Neuroinflammation; Ziconotide.
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