Antioxidant AWOL in ALS, Precursor Fights Stroke

Antioxidants are key recruits in the body’s battle against aging and degeneration—and new evidence suggests that at least some of these foot soldiers are missing in amyotrophic lateral sclerosis. Scientists at the Tel Aviv Sourasky Medical Center report, in the June 22 Journal of Neurological Science online, that people with ALS have lower serum levels of the antioxidant uric acid than do age-matched controls. In addition, the researchers linked the greatest differences in uric acid to a steeper decline in disease progression. The research suggests that boosting uric acid might help ALS patients. Some support for the benefit of uric acid comes from another paper, published June 24, in the Journal of Neuroscience. Researchers from Harvard Medical School in Boston describe the use of inosine—which the body can convert into uric acid—as a treatment for stroke in rats.

Acid Off Base

Lowered uric acid levels have been found in people with Parkinson disease (see ARF related news story; Schwarzschild et al., 2008; Weisskopf et al., 2007), and several antioxidants are diminished in Alzheimer disease (Kim et al., 2006). To see if the same was true in ALS, first author Daniel Keizman, senior author Vivian Drory, and colleagues assessed serum uric acid levels in 86 patients and 86 controls matched for gender, age, and body mass index. Control participant serum averaged 5.76 mg/dl uric acid; in people with ALS it averaged less at 4.78 mg/dl.

The authors also looked for a relationship between uric acid levels and the ALS Functional Rating Scale, which scores patients on ability to carry out tasks such as dressing and eating. While they found no direct link between uric acid levels and functional score, they did discover a relationship between two statistics: ΔUA, the difference between a patient’s uric acid level and that of the matched control; and ΔFRS, the rate of change in the functional score between two assessments approximately six months apart (46 patients returned for the second assessment). That is, those patients who had much lower uric acid levels than their control partners lost the most functionality over time.

Our results could have several implications, Drory wrote in an e-mail to ARF. For one, people with ALS who also have high uric acid levels from a second condition such as gout might not benefit—and might even suffer—from therapies designed to reduce uric acid. Second, she wrote: Drugs that raise the level of uric acid might be effective in lowering the rate of disease in ALS.

There are many ways that uric acid levels could correlate with ALS, wrote Marc Weisskopf of the Harvard School of Public Health, who was not involved in the study, in an e-mail to ARF. The lowered antioxidants could contribute to disease or be a side effect. For example, he suggested, diet is a factor in uric acid levels. So if diets changed among the cases with ALS, could it be that those dietary changes led to the lower uric acid levels

Purine on Point

If indeed uric acid-directed therapeutics could benefit people with ALS, the purine nucleoside inosine, a uric acid precursor, would be a prime candidate. Inosine has been shown to protect neurons if given to rats before they undergo surgery to cause stroke (Shen et al., 2005) and it activates the protein kinase Mst3b, part of a pathway that releases trophic factors to promote axon outgrowth (Irwin et al., 2006). In the current Journal of Neuroscience study, first author Laila Zai, principal investigator Larry Benowitz, and colleagues show that it also promotes axon growth when given to rats after ischemia and restores fine motor movements.

Zai and colleagues targeted the ischemia to the sensorimotor cortex on one side of the brain. To make a focused lesion, they injected animals with a photosensitive dye, Rose Bengal, then opened the cranium to shine light on one particular spot. The light caused the dye to release free radicals, damaging nearby cells and causing platelets to aggregate, leading to ischemia. Some lesioned rats were then treated with inosine, others received saline solution. Then, the scientists sacrificed some animals and used microscopy to look for new axon growth between the undamaged side of the brain and the ipsilateral side of the body—that is, when the left brain was lesioned, they looked for new connections between the right side of the brain and the right side of the body, or between left brain and left body when the right side was lesioned. Since there are normally very few ipsilateral connections, they could assume that any such networks were new. The researchers counted these ipsilateral axon fibers and found that the inosine-treated animals had triple the new connections of the saline-treated controls. It is possible that other connections also regrew, Benowitz said, but those would not be as obvious.

The researchers monitored fine motor control by training the rats, before surgery, to reach through a slit into a Plexiglas box to retrieve a banana-flavored pellet. Immediately after surgery, all animals showed severely diminished ability to collect the food pellets with the forepaw opposite the damaged hemisphere. After a few weeks, saline-treated animals recovered 35-40 percent of their pre-surgery ability. The inosine-treated animals recovered 80 percent, suggesting that those new connections they were growing translated directly into fine motor functioning.

Inosine had no effect on animals that had not undergone the lesioning treatment, so Benowitz thinks the nucleoside must augment the body’s natural recovery process. In addition to its role in promoting axon outgrowth via Mst3b, inosine has been shown to suppress neurons’ response to toxic glutamate, limit inflammation (Hask et al., 2000), and protect astrocytes from hypoxia (Jurkowitz et al., 1998). In the case of stroke treatment, it is not clear if inosine itself, or a downstream product—such as uric acid—is the active player.

For stroke, Benowitz thinks inosine treatment is nearly ready for prime time. We’re hoping that what we’re discovering in animals can move into the clinic, he said, although he noted that given the heterogeneity of stroke patients, any trial would have to be large-scale, and the effect considerable, to rise above random noise in the data.

For ALS, there is more work to do before uric acid, or inosine, hits the clinic. Drory plans to test drugs that increase uric acid in a mouse model of ALS. I think the results are very suggestive and definitely worth following up with other studies, Weisskopf wrote.

Keizman D, Ish-Shalom M, Berliner S, Maimon N, Vered Y, Artamonov I, Tsehori J, Nefussy B, Drory VE. Low uric acid levels in serum of patients with ALS: Further evidence for oxidative stress J Neurol Sci. 2009 Jun 22. Abstract

Zai L, Ferrari C, Subbaiah S, Havton LA, Coppola G, Strittmatter S, Irwin N, Geschwind D, Benowitz LI. Inosine alters gene expression and axonal projections in neurons contralateral to a cortical infarct and improves skilled use of the impaired limb. J Neurosci. 2009 Jun 24;29(25):8187-97. Abstract

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