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. 2014 Apr 30:566:286-91.
doi: 10.1016/j.neulet.2014.02.058. Epub 2014 Mar 15.

7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis

Orhan Tansel Korkmaz  1 , Nurgul Aytan  2 , Isabel Carreras  3 , Ji-Kyung Choi  4 , Neil W Kowall  2 , Bruce G Jenkins  4 , Alpaslan Dedeoglu  5
Affiliations

7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis

Orhan Tansel Korkmaz et al. Neurosci Lett. .

Abstract

Amyotrophic lateral sclerosis (ALS) is an enigmatic neurodegenerative disorder without any effective treatment characterized by loss of motor neurons (MNs) that results in rapidly progressive motor weakness and early death due to respiratory failure. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family known to play a prominent role in the differentiation and survival of MNs. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) is a potent and selective small molecule tyrosine kinase receptor B (TrkB) agonist that mimics the effects of BDNF. In the present study, we evaluated the neuroprotective effects of 7,8-DHF in a transgenic ALS mouse model (SOD1(G93A)). We found that chronic administration of 7,8-DHF significantly improved motor deficits, and preserved spinal MNs count and dendritic spines in SOD1(G93A) mice. These data suggest that 7,8-DHF should be considered as a potential therapy for ALS and the other motor neuron diseases.

Keywords: 7,8-Dihydroxyflavone; Amyotrophic lateral sclerosis; BDNF; Motor neurons; TrkB.

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Conflict of interest statement

Conflict of Interest: The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Effects of 7,8-DHF treatment (5mg/kg, i.p.) on body weight and motor performance in ALS mice (SOD1G93A). Starting at one month of age and until 105 days of age, body weight and motor performance were monitored twice a week. A, Body weight loss of ALS mice is not reversed by 7, 8-DHF. B, 7,8-DHF treatment improved motor performance of ALS mice up to the level of wild type (WT) mice (Repeated measures multi-way ANOVA, followed by the Dunns test for posthoc comparisons, *p<0.001 as compared to the other groups, n=10).
Figure 2
Figure 2
Effect of 7,8-DHF treatment (5mg/kg, i.p.) on motor neurons count in the ventral horn of lumbar cord in ALS mice (SOD1G93A). Stereological methods were employed to quantify the number of motor neurons. Neurons were marked with two different marker depending on size, 30μm diameter or larger and smaller than 30μm but larger than 15μm. A, B, C, D, Photomicrographs displaying Cresyl violet (CV) staining of WT-Saline (A), WT-7,8-DHF (B), ALS-Saline (C), and ALS-7,8-DHF (D). Magnifications for CV staining photomicrographs x10 (lower panels) and x60 (upper panels). Red arrows show MNs larger than 30μm, yellow arrows show MNs smaller than 30μm but larger than 15μm. E, F, G, MNs count in 7,8-DHF treated and untreated ALS mice (SOD1G93A) and WT mice. E, 7,8-DHF treatment significantly increased total MNs count in ALS group. F, 7,8-DHF treatment significantly increased small MNs (15–30μm) count in ALS group. G, 7,8-DHF treatment did not change large MNs (>30μm) count in ALS group (One-way ANOVA, followed by Tukey’s HSD test for multiple comparisons. *p<0.001 and #p<0.01, as compared to the other groups, n=10).
Figure 3
Figure 3
Effect of 7,8-DHF treatment (5mg/kg, i.p.) on dendritic spine density of motor neurons in the ventral horn of lumbar cord in ALS mice (SOD1G93A). Photomicrographs displaying Golgi staining of WT-Saline (A), WT-7,8-DHF (B), ALS-Saline (C), and ALS-7,8-DHF (D). Magnifications for photomicrographs x100. Spines were counted in 25μm length of secondary branches branch for (red line in figure A). While untreated ALS mice (C) have lesser spines than WT, 7,8-DHF treated ALS mice (D) have as much as WT mice (A,B). E, 7,8-DHF treatment significantly increased spine density in ALS group (One-way ANOVA, followed by Tukey’s HSD test for multiple comparisons. *p<0.001, as compared to the other groups, n=10).
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