Neuroactive Neurosteroids as Endogenous Effectors for the Sigma_1(σ_1)Receptor : Pharmacological Evidence and Therapeutic Opportunities

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Author(s)

Abstract

Neuroactive neurosteroids, including progesterone, allopregnanolone, pregnenolone and dehydroepiandrosterone, represent steroid hormones synthesized <I>de novo</I> in the brain and acting locally on nervous cells. Neurosteroids modulate several neurotransmitter systems such as γ-aminobutyric acid type A (GABA<SUB>A</SUB>), <I>N</I>-methyl-D-aspartate (NMDA) and acetylcholine receptors. As physiologic consequences, they are involved in neuronal plasticity, learning and memory processes, aggression and epilepsy, and they modulate the responses to stress, anxiety and depression. The σ<SUB>1</SUB>-receptor protein was recently purified and its cDNA was cloned in several species. The amino-acid sequences are structurally unrelated to known mammalian proteins, but shared homology with a fungal sterol C<SUB>8</SUB>-C<SUB>7</SUB> isomerase. The σ<SUB>1</SUB>-receptor ligands exert a potent neuromodulation on excitatory neurotransmitter systems, including the glutamate and cholinergic systems. Consequently, selective σ<SUB>1</SUB> agonists show neuroprotective properties and beneficial effects in memory processes, stress and depression. The evidence of a direct interaction between neurosteroids and σ<SUB>1</SUB> receptors was first suggested by the ability of several steroids to inhibit the binding of σ<SUB>1</SUB>-receptor radioligands in vitro and in vivo. A crossed pharmacology between neurosteroids and σ<SUB>1</SUB>-receptor ligands was described in several physiological tests and behavioral responses. This review will detail the recent evidence for a common mechanism of action between neurosteroids and σ<SUB>1</SUB>-receptor ligands and focus on the potential therapeutic interests of such interaction in the physiopathology of learning and memory impairments, stress, depression and neuroprotection.

Journal

  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 81(2), 125-155, 1999-10

    The Japanese Pharmacological Society

References:  299

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Cited by:  6

Codes

  • NII Article ID (NAID)
    10008196418
  • NII NACSIS-CAT ID (NCID)
    AA00691188
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    00215198
  • NDL Article ID
    4886611
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z53-D199
  • Data Source
    CJP  CJPref  NDL  J-STAGE 
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