Drug/nutrition interaction in the developing brain: Dipyrone enhances spreading depression in rats

Abstract

The abuse of pharmaceutical drugs and the inadequate ingestion of nutrients constitute external factors that can alter brain development, both individually and in combination. We used cortical spreading depression (CSD) as a neurophysiological parameter to investigate the combined effects of the antipyretic/analgesic/anti-inflammatory drug dipyrone and malnutrition (M) in the developing rat brain. Suckling malnourished rats (M; n = 69) and well nourished controls (W; n = 76) received dipyrone (300 mg/kg/day) or saline per gavage for 7 consecutive days during the 2nd, 3rd, or 4th postnatal week. At 35–45 days, CSD was recorded at 2 points in the parietal region. In both groups, dipyrone increased CSD propagation velocities compared to respective saline controls ( P < 0.05). This effect was intensified when dipyrone application during the 4th postnatal week intensified the increase compared to the 2nd and 3rd weeks. In saline-treated groups, the velocities (mean ± s.d., in mm/min) were 3.70 ± 0.11, 3.77 ± 0.16, and 3.78 ± 0.13 (W) and 4.13 ± 0.10, 4.16 ± 0.10, and 4.14 ± 0.09 (M), for animals treated in the 2nd, 3rd and 4th postnatal weeks. In dipyrone-treated groups, the respective values were 3.99 ± 0.14, 4.03 ± 0.16, and 4.30 ± 0.19 (W) and 4.47 ± 0.17, 4.70 ± 0.31, and 5.01 ± 0.28 (M). Results support the hypothesis that dipyrone has a CSD-facilitating effect, which is more intense at a late brain developmental stage and is facilitated by malnutrition. This may help explain the developmental brain excitability changes that are associated with pharmacological and nutritional factors.