Physiological and pathological processes of synaptic plasticity and memory in drug discovery: Do not forget the dose-response curve

Jos Prickaerts, Nick P. Van Goethem, Walter Gulisano, Elentina K. Argyrousi, Agostino Palmeri, Daniela Puzzo*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Web of Science)
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Abstract

The response of a biological system to an endogenous or exogenous molecule depends upon the dose. For this reason, performing dose-response curves is crucial to understand physiological and pathophysiological phenomena, and to predict the effect of a drug. Most of the studies in pharmacological research have been performed according to the classical threshold model, focusing on higher doses able to ensure a biological effect. However, recent evidences pointed out the need to investigate the effect of low doses. Indeed, several molecules behave in a hormetic fashion, i.e. low-doses stimulate whereas high-doses inhibit a biological response. This is particularly interesting in CNS, where several physiological molecules involved in neuronal transmission during learning and memory have shown a biphasic effect that might represent the link between physiology and pathology.

In this review we will focus on cholinergic, glutamatergic and nitrinergic transmission, because of their central role in learning and memory and their impairment in neurodegenerative disorders such as Alzheimer's disease.

Pre-clinical studies performed on healthy adult animals and aged animals, as well as transgenic animal models of AD, have suggested a biphasic DR for acetylcholine, glutamate and nitric oxide. This stresses the relevance to perform DR curves when studying the mechanisms underlying synaptic plasticity and memory, the pharmacological profile of cognitive-enhancing drugs acting on these systems, and the possibility to combine low/ineffective doses of drugs that might have additive/synergistic effects, reducing the unwanted side effects associated to the high doses.

Original languageEnglish
Pages (from-to)59-70
Number of pages12
JournalEuropean Journal of Pharmacology
Volume817
DOIs
Publication statusPublished - 15 Dec 2017

Keywords

  • Dose-response curves
  • Synaptic plasticity
  • Memory
  • Alzheimer's disease
  • Cognitive-enhancing drugs
  • Low doses
  • NITRIC-OXIDE SYNTHASE
  • NICOTINIC ACETYLCHOLINE-RECEPTORS
  • LONG-TERM POTENTIATION
  • OBJECT RECOGNITION MEMORY
  • CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES
  • RANDOMIZED CONTROLLED-TRIAL
  • CENTRAL-NERVOUS-SYSTEM
  • CEREBRAL-BLOOD-FLOW
  • PROTEIN-KINASE-A
  • LATE-PHASE LTP

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