d ‐Pinitol promotes tau dephosphorylation through a cyclin‐dependent kinase 5 regulation mechanism: A new potential approach for tauopathies?
British J Pharmacology. 2022-07-18; 179(19): 4655-4672
DOI: 10.1111/bph.15907
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Medina-Vera D(1)(2)(3)(4), Navarro JA(1)(3), Rivera P(1), Rosell-Valle C(1),
Gutiérrez-Adán A(5), Sanjuan C(6), López-Gambero AJ(1)(2), Tovar R(1)(3), Suárez
J(1)(7), Pavón FJ(1)(4), Baixeras E(8), Decara J(1), Rodríguez de Fonseca F(1).
Author information:
(1)Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario
Regional de Málaga, UGC Salud Mental, Málaga, Spain.
(2)Facultad de Ciencias, Universidad de Málaga, Málaga, Spain.
(3)Facultad de Medicina, Universidad de Málaga, Málaga, Spain.
(4)Instituto de Investigación Biomédica de Málaga-IBIMA and CIBER Enfermedades
Cardiovasculares (CIBERCV), Hospital Universitario Virgen de la Victoria, UGC
del Corazón, Málaga, Spain.
(5)Departamento de Reproducción Animal, Instituto Nacional de Investigación y
Tecnología Agraria y Alimentaria (INIA), Madrid, Spain.
(6)Euronutra S.L., Parque Tecnológico de Andalucía, Málaga, Spain.
(7)Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia,
Universidad de Málaga, Málaga, Spain.
(8)Departamento de Bioquímica y Biología Molecular, Facultad de Medicina,
Universidad de Málaga, Málaga, Spain.
BACKGROUND AND PURPOSE: Recent evidence links brain insulin resistance with
neurodegenerative diseases, where hyperphosphorylated tau protein contributes to
neuronal cell death. In the present study, we aimed to evaluate if d-pinitol
inositol, which acts as an insulin sensitizer, affects the phosphorylation
status of tau protein.
EXPERIMENTAL APPROACH: We studied the pharmacological effect of d-pinitol on
insulin signalling and tau phosphorylation in the hippocampus of Wistar and
Zucker rats. To this end, we evaluated by western blotting the Akt pathway and
its downstream proteins as being one of the main insulin-mediator pathways.
Also, we explored the functional status of additional kinases phosphorylating
tau, including PKA, ERK1/2, AMPK and CDK5. We utilized the 3xTg mouse model as a
control for tauopathy, since it carries tau mutations that promote
phosphorylation and aggregation.
KEY RESULTS: Surprisingly, we discovered that oral d-pinitol treatment lowered
tau phosphorylation significantly, but not through the expected kinase GSK-3
regulation. An extensive search for additional kinases phosphorylating tau
revealed that this effect was mediated through a mechanism dependent on the
reduction of the activity of the CDK5, affecting both its p35 and p25 subunits.
This effect disappeared in leptin-deficient Zucker rats, uncovering that the
association of leptin deficiency, obesity, dyslipidaemia and
hyperinsulinaemia abrogates d-pinitol actions on tau phosphorylation. The 3xTg
mice confirmed d-pinitol effectiveness in a genetic AD-tauopathy.
CONCLUSION AND IMPLICATIONS: The present findings suggest that d-pinitol, by
regulating CDK5 activity through a decrease of CDK5R1, is a potential drug for
developing treatments for neurological disorders such as tauopathies.
© 2022 The Authors. British Journal of Pharmacology published by John Wiley &
Sons Ltd on behalf of British Pharmacological Society.
DOI: 10.1111/bph.15907
PMCID: PMC9544772
PMID: 35760415 [Indexed for MEDLINE]
Conflict of interest statement: Carlos Sanjuan declares he receives salary and
has shares in Euronutra Company. The remaining authors declare that they have no
known competing financial interest or personal relationships that could have
appeared to influence the work reported in this paper.