Tranilast, a Transient Receptor Potential Vanilloid 2 Channel (TRPV2) Inhibitor Attenuates Amyloid β-Induced Cognitive Impairment: Possible Mechanisms

Neuromolecular Med. 2022 Jun;24(2):183-194. doi: 10.1007/s12017-021-08675-x. Epub 2021 Jul 6.

Abstract

Alzheimer's disease (AD) is associated with the accumulation of β-amyloid and leads to cognitive impairment. Numerous studies have established that neuronal calcium homeostasis is perturbed in AD. Recently, transient receptor potential vanilloid 2 (TRPV2) channels, a non-selective calcium-permeable channel, have been investigated in several diseases. However, the role of the TRPV2 channel has not been investigated in AD yet. In this study, intracerebroventricular administration of β-amyloid (10 μg) to Sprague Dawley rats resulted in cognitive impairment which was evident from the assessment of cognitive tests. Also, TRPV2 mRNA and protein expression were found to be upregulated, while the expression of Ca2+/calmodulin-dependent protein kinase II (p-CaMKII-Thr-286), glycogen synthase kinase 3β (p-GSK-3β-Ser-9), cAMP response element-binding protein (p-CREB-Ser-133), and postsynaptic density protein 95 (PSD-95) were downregulated in the hippocampus of β-amyloid-treated animals. Even, β-amyloid-treated animals showed upregulation of mRNA level of calcium buffering proteins (parvalbumin and calsequestrin) and calcineurin A (PPP3CA) in the hippocampus. Acetylcholinesterase activity was also increased in the cortex of β-amyloid-treated animals. Three-week treatment with tranilast showed improvement in the cognitive parameters which was associated with a decrease in TRPV2 expression and AChE activity. Additionally, an increase in the protein expression of p-CaMKII, p-GSK-3β, p-CREB and PSD-95 in the hippocampus was found. Downregulation in the mRNA level of calcium buffering proteins (parvalbumin and calsequestrin) and calcineurin A in the hippocampus was also seen. These results reveal the importance of TRPV2 channels in the β-amyloid-induced cognitive deficits and suggest TRPV2 as a potential target for AD.

Keywords: Alzheimer’s disease; Calcium; Cognition; Tranilast; Transient receptor potential vanilloid 2 (TRPV2); β-amyloid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease* / drug therapy
  • Amyloid beta-Peptides / adverse effects
  • Animals
  • Calcineurin / metabolism
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Calsequestrin
  • Cognitive Dysfunction* / chemically induced
  • Cognitive Dysfunction* / drug therapy
  • Glycogen Synthase Kinase 3 beta
  • Parvalbumins
  • RNA, Messenger / genetics
  • Rats
  • Rats, Sprague-Dawley
  • TRPV Cation Channels* / metabolism
  • ortho-Aminobenzoates

Substances

  • Amyloid beta-Peptides
  • Calsequestrin
  • Parvalbumins
  • RNA, Messenger
  • TRPV Cation Channels
  • Trpv2 protein, rat
  • ortho-Aminobenzoates
  • Glycogen Synthase Kinase 3 beta
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Acetylcholinesterase
  • Calcineurin
  • tranilast
  • Calcium