Omega-3 Hastens and Omega-6 Delays the Progression of Neuropathology in a Murine Model of Familial ALS

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a progressive disease of motor neurons that has no cure or effective treatment. Any approach that could sustain minor motor function during terminal stages would improve quality of life.

Objective: We examined the impact of omega-3 (Ω-3) and Ω-6, on motor neuron function in mice expressing mutant human superoxide dismutase-1 (SOD-1), which dominantly confers familial ALS and induces a similar sequence of motor neuron decline and eventual death when expressed in mice.

Method: Mice received standard diets supplemented with equivalent amounts of Ω-3 and Ω-6 or a 10x increase in Ω-6 with no change in Ω-3 commencing at 4 weeks of age. Motor function and biochemical/histological parameters were assayed by standard methodologies.

Results: Supplementation with equivalent Ω-3 and Ω-6 hastened motor neuron pathology and death, while 10x Ω-6 with no change in Ω-3 significantly delayed motor neuron pathology, including preservation of minor motor neuron function during the terminal stage.

Conclusion: In the absence of a cure or treatment, affected individuals may resort to popular nutritional supplements such as Ω-3 as a form of "self-medication". However, our findings and those of other laboratories indicate that such an approach could be harmful. Our findings suggest that a critical balance of Ω-6 and Ω-3 may temporarily preserve motor neuron function during the terminal stages of ALS, which could provide a substantial improvement in quality of life for affected individuals and their caregivers.

Keywords: Amyotrophic lateral sclerosis; Inflammation; Motor neuron; Neuropathology; Omega-3; Omega-6.

Fig. (1)

Ω-6 delayed motor neuron decline. Mice maintained on the indicated diets commencing at 4 weeks of age were subjected to motor function assays at the indicated ages. The 1000xΩ-3,6 diet (Yip et al., 2013) hastened, while the 10xΩ-6 diet delayed, the 50% Survival point (panel C; p<0.05 for both, ANOVA asterisks) as compared to the standard diet (with no supplementation with either Ω). The 10xΩ-6 diet significantly (p<0.05; Student’s t tests; asterisks) sustained motor function for 1-1.5 weeks longer than the 4xΩ-3,6 as assayed by Motor Deficit (panel B), Quadrant test (panel C, trend lines calculated via Excel) and overall Activity (panel D).

Fig. (2)

Ω-3 and Ω-6 altered reactive astrocytes and motor neuron number Representative sections of lumbar spinal cord of mice receiving the indicated diets for 1 week. Sections were reacted with anti-GFAP and SMI-32 (to reveal reactive astrocytes and motor neurons, respectively). The accompanying graphs present quantification of immunoreactivity from 10 sections from multiple cords. *p<0.05.

Fig. (3)

Ω-3 and Ω-6 altered microglial activation.

Fig. (4)

LC-MS analyses of TXB₂, PGD₂ and PGE₂ standards and in homogenates of lumbar cord harvested after 1 week on indicated diets (“pre-symptomatic”) or following sacrifice at terminal stage (“Terminal). The accompanying graphs present the area under the curves to facilitate comparison. All three compounds increased >2-fold for mice maintained on the 10xΩ-6 diet; TXB₂ did not increase for mice maintained on the 4xΩ-3,6 diet.