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GABAergic drugs become neurotoxic in cortical neurons pre-exposed to brain-derived neurotrophic factor

Gemma Molinaro1, Giuseppe Battaglia, Barbara Riozzi

  • 1Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy.

Molecular and Cellular Neurosciences
|December 7, 2007
PubMed

Insights

Brain-derived neurotrophic factor (BDNF) alters GABAergic drug effects, potentially causing neurotoxicity. This study reveals how BDNF impacts neuronal responses to GABAergic agents, highlighting risks in conditions with elevated BDNF.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pharmacology

Background:

  • Brain-derived neurotrophic factor (BDNF) plays a crucial role in neuronal survival, growth, and plasticity.
  • GABAergic neurotransmission is the primary inhibitory system in the central nervous system.
  • Dysregulation of GABAergic signaling is implicated in various neurological disorders.

Purpose of the Study:

  • To investigate the effect of BDNF pretreatment on N-methyl-D-aspartate (NMDA)-induced excitotoxicity in cultured mouse cortical cells.
  • To determine how BDNF influences the neuroprotective or neurotoxic effects of GABAergic drugs.
  • To elucidate the underlying mechanisms, particularly the role of anion reversal potential and KCC2 transporter expression.

Main Methods:

  • Primary mouse cortical cell cultures were pretreated with BDNF.
  • Cells were challenged with NMDA to induce excitotoxicity.
  • The effects of GABAergic drugs (antagonists and agonists) and changes in chloride ion concentrations were assessed.
  • Expression of the K(+)/Cl(-) co-transporter, KCC2, was measured.

Main Results:

  • BDNF pretreatment enhanced NMDA-induced excitotoxic neuronal death.
  • GABA(A) receptor antagonists became neuroprotective after BDNF pretreatment, while agonists amplified NMDA toxicity.
  • These effects were linked to altered anion reversal potential, increased chloride efflux, and reduced KCC2 expression following BDNF exposure.

Conclusions:

  • BDNF significantly alters the functional impact of GABAergic drugs on neuronal excitability and survival.
  • GABAergic drugs, typically protective, can become neurotoxic in the presence of BDNF due to changes in chloride homeostasis.
  • These findings suggest potential risks of GABAergic drug neurotoxicity in conditions characterized by elevated BDNF levels.

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