On the inhibitory affect of some dementia drugs on DNA polymerase Beta activity

Neurochem Res. 2008 Nov;33(11):2187-96. doi: 10.1007/s11064-007-9587-3. Epub 2008 Jan 10.

Abstract

Some drugs are routinely prescribed for dementia that sets in either due to normal ageing or due to neurodegenerative disorders. We have studied the effect of three of these drugs, Donepezil hydrochloride, Rivastigmine tartrate and Nootropyl, on the activity of DNA polymerases beta, a crucial enzyme in the base excision repair pathway, the most important mode of DNA repair in brain. All the three drugs inhibited DNA polymerase beta activity to varying degrees although the affects of Donepezil being the least and inconsistent. The drugs preferentially bind to and inhibit the activities of 8 kDa domain of DNA polymerase beta that is known to possess the dRP lyase activity. The function of 31 kDa domain dealing with template driven addition of nucleotides at 3' end of the primer is not adversely affected. The inhibitory action of most widely used dementia drugs on DNA repair potential signifies that pharma sector needs to consider this aspect especially while designing drugs targeted towards brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • DNA Polymerase beta / metabolism*
  • DNA Primers
  • DNA Repair
  • Dementia / drug therapy*
  • Molecular Structure
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Rats

Substances

  • DNA Primers
  • Neuroprotective Agents
  • DNA Polymerase beta