Neuropharmacology and analgesia
Marked diversity in the action of growth factors on N-methyl-d-rmaspartate-induced neuronal degeneration

https://doi.org/10.1016/0014-2999(96)00225-7Get rights and content

Abstract

Neuronal degeneration was induced in cultured rat hippocampal neurons by a 20-min exposure to the glutamatergic agonist, N-methyl-d-aspartate (NMDA; 100 μM), and the neuroprotective activity of a set of growth factors and cytokines was compared. During the early stages of degeneration, NMDA induced changes that were characteristic of neuronal necrosis, including swelling and darkening of the neuronal soma and swelling of neurites, leading to the formation of beaded varicosities (‘blebs’). These changes were followed by nuclear pyknosis, formation of double-stranded DNA breaks and loss of membrane integrity. Only transforming growth factor-β1 (TGF-β1; 1–10 ng/ml) and tumor necrosis factor-α (TNF-α; 30 ng/ml) protected the hippocampal neurons against NMDA neurotoxicity after short-term (60 min) pre-treatments. Interleukin-1β (10–100 ng/ml) and fibroblast growth factor-2 (FGF-2; 50 ng/ml) were clearly effective when administered 24 h prior to the NMDA exposure, but not when given 60 min before the insult. Interestingly, the protective effect of interleukin-1β was significantly reduced in the presence of a neutralizing antibody to TGF-β. Of note, short-term pre-treatment with brain-derived neurotrophic factor (BDNF; 5–50 ng/ml) significantly potentiated NMDA-induced neurodegeneration. These experiments demonstrate marked diversity in the actions of growth factors on NMDA-induced neuronal degeneration.

References (42)

Cited by (35)

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    In agreement with that, Koh et al. (1995) demonstrated that BDNF treatment markedly potentiates necrotic death induced by exposure to oxygen-glucose deprivation or N-methyl-d-aspartate (NMDA) in murine cortical cell cultures. Accordingly, short-term pretreatment with BDNF significantly potentiates NMDA-induced neurodegeneration (Prehn, 1996). The molecular mechanisms may be related to effects of BDNF on ion channels, since it can trigger depolarization of neurons by activating the sodium channel (Blum et al., 2002) and induces calcium release from the endoplasmic reticulum via a pathway activated by a trkB receptor (Rose et al., 2003).

  • Effect of a neuroprotective exercise protocol on oxidative state and BDNF levels in the rat hippocampus

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    However, there is also evidence that BDNF may increase neuronal vulnerability to excitotoxicity. Koh et al. (1995) demonstrated that treatment with BDNF markedly potentiated necrotic death induced by exposure to oxygen–glucose deprivation or N-methyl-d-aspartate (NMDA) in murine cortical cell cultures, as well as, short-term pretreatment with BDNF significantly potentiate NMDA-induced neurodegeneration (Prehn, 1996). The molecular mechanisms may be related to the action of BDNF on ions channels, since BDNF can trigger depolarization of neurons by activating the sodium channel (Blum et al., 2002) and produce calcium release from the endoplasmic reticulum via a pathway activated by a trkB receptor (Rose et al., 2003).

  • Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons

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    Nevertheless, our experiments and those of Abe et al. (2003) do suggest that whether agmatine exerts neuroprotection or neurotoxicity partly depends on the experimental conditions, including the concentrations of K+ and agmatine applied. The ability of NMDA to induce apoptosis in cultured hippocampal neurons has been well documented (Diebaili et al., 2002; Vincent et al., 2002; Kajta et al., 2004; Prehn, 1996; Lee et al., 2003). Therefore, the NMDA induced neuronal death observed in the present study might also be due to apoptosis.

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