Expression profile of rat hippocampal neurons treated with the neuroprotective compound 2,4-dinitrophenol: up-regulation of cAMP signaling genes.
2,4-Dinitrophenol (DNP) is classically known as a mitochondrial uncoupler and, at high concentrations, is toxic to a variety of cells. However, it has recently been shown that, at subtoxic concentrations, DNP protects neurons against a variety of insults and promotes neuronal differentiation and neuritogenesis. The molecular and cellular mechanisms underlying the beneficial neuroactive properties of DNP are still largely unknown. We have now used DNA microarray analysis to investigate changes in gene expression in rat hippocampal neurons in culture treated with low micromolar concentrations of DNP. Under conditions that did not affect neuronal viability, high-energy phosphate levels or mitochondrial oxygen consumption, DNP induced up-regulation of 275 genes and down-regulation of 231 genes. Significantly, several up-regulated genes were linked to intracellular cAMP signaling, known to be involved in neurite outgrowth, synaptic plasticity, and neuronal survival. Differential expression of specific genes was validated by quantitative RT-PCR using independent samples. Results shed light on molecular mechanisms underlying neuroprotection by DNP and point to possible targets for development of novel therapeutics for neurodegenerative disorders.
Sebollela
Adriano
A
Instituto de Bioquímica Médica, Programa de Bioquímica e Biofísica Celular, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21944-590, Brazil.
Freitas-Corrêa
Léo
L
Oliveira
Fábio F
FF
Mendes
Camila T
CT
Wasilewska-Sampaio
Ana Paula
AP
Camacho-Pereira
Juliana
J
Galina
Antonio
A
Brentani
Helena
H
Passetti
Fabio
F
De Felice
Fernanda G
FG
Dias-Neto
Emmanuel
E
Ferreira
Sérgio T
ST
D019297:2,4-Dinitrophenol / Q000494:pharmacology*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects*
D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D019297:2,4-Dinitrophenol