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Neurology Today:
doi: 10.1097/01.NT.0000407798.78711.6b
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Enzyme Injections Show Promise for Diabetic Neuropathy

Collins, Thomas R.

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Intramuscular injection of nicotinamide mononucleotide improved sensory function in diabetic rats with neuropathy, reduced the slowing of the conduction of motor nerves in the rats, and prevented the loss of nerve fibers in the skin.

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SAN DIEGO—Injection of a substance involved in cell metabolism appears to lessen the severity of diabetic neuropathy, at least over a short period of time, in a rat model, researchers said here at the American Neurological Association annual meeting in late September.

Intramuscular injection of nicotinamide mononucleotide (NMN) improved sensory function in diabetic rats with neuropathy, reduced the slowing of the conduction of motor nerves in the rats, and prevented the loss of nerve fibers in the skin, the findings show.

NMN is important because it is a precursor to the generation of nicotinamide adenine dinucleotide (NAD), a coenzyme crucial to the energy-production activity of mitochondria in the cell. It is believed that increased production of mitochondrial reactive oxygen species — brought about by hyperglycemia — is an important factor in co-morbidities associated with diabetes.

“NAD metabolism is abnormal in human diabetes and therefore there's a very good rationale, then, for increasing NAD levels in diabetes … potentially this could be a therapy for human diabetic neuropathy,” said James W. Russell, MD, professor of neurology at the University of Maryland School of Medicine.

The study — funded by the Juvenile Diabetes Research Foundation, the NIH, and the Department of Veterans Affairs — included six non-diabetic rats, six diabetic rats that received no treatment, six diabetic rats on 50 mg/kg of NMN, and six diabetic rats on 100 mg/kg of NMN. The drug was injected into muscle tissue every other day.

After two months of treatment, the treated groups performed better than the untreated diabetic group on various sensory functions — the quickness of response to hair touching its paws (p<.05 between 100 mg treatment and the non-treated diabetics) and response to a heat stimulus (p<.01 for the same groups).

Also after the treatment period, sciatic motor nerve conduction velocity was significantly better in both treated groups than the non-treated diabetic group (p<.001), as was tail motor nerve conduction velocity (p<.01 for the 100 mg group compared to the non-treated diabetics).

NMN treatment also reduced the loss of epidermal nerve fibers in non- treated diabetic animals (p<.01). NMN at a dose of 100 mg/kg significantly increased intraepidermal nerve fiber density.

Researchers also found that the addition of NMN to adult dorsal root ganglion neurons reduced glucose–induced oxidative stress. Particularly encouraging, Dr. Russell said, is that NMN was found to upregulate SIRT1 a protein present in cells and also in mitochondria, where it may regulate mitochondrial respiration. SIRT1 activates PGC-1a, a transcription stimulator that regulates mitochondrial activity. It is thought, then, that NMN might help activate mitochondrial metabolic and anti-oxidant pathways that protect against neuronal injury caused by hyperglycemia, a risk factor for diabetes.

“This is, in fact, potentially a very important role for this medication,” he said. “It opens up the possibility that this upregulation of SIRT1 may in fact have a sustained benefit in diabetic neuropathy even beyond the duration of treatment.”

DR. EVA FELDMAN said...
DR. EVA FELDMAN said...
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The treatment did not have significant adverse effects, which, Dr. Russell said, is not surprising as NAD is naturally found in animal and human cells.

But he cautioned that further studies need to be conducted in animals and then the therapy evaluated in human studies to determine if NMN or related medications would be effective in the treatment of human diabetic neuropathy.

Work on NMN continues, he said. “What we're looking at, and we have funding for this, is to see whether or not we can reverse diabetic neuropathy” in rats or mice with chronic NMN treatment, he said.

Researchers are also investigating the possibility of less frequent dosing. “This drug doesn't have to be given every day,” he said. “We're now looking at the possibility of giving this over a more extended period, perhaps every few days or once a week.”

For clinical trials, the investigators said they would assume subcutaneous injections of NMN would be possible, but they are only investigating that possibility now.

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EXPERTS COMMENT

DR. JAMES W. RUSSELL...
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Eva Feldman, MD, PhD, professor of neurology at the University of Michigan, said the possibility of regeneration of nerve fibers is particularly encouraging.

“Not only do you ameliorate or stop the normal damage one sees in diabetes but what his data are showing is you may see enhancement or regeneration,” she said. “Most of the drugs that we've used in the past for the treatment of diabetic neuropathy have just tried to arrest or halt the progression of this disorder, because it's a relentless, continuous progression.”

She noted, though, that the animals used in the study had more severe diabetes than people typically have — the diabetic rats had blood glucose levels of greater than 300 mg/dL, more than twice the threshold for diabetes in human diabetics.

“They looked like they were quite ill, more ill than you would normally see in a patient,” Dr. Feldman said. “So it's a different sort of animal model system and it doesn't correlate that well, to a certain extent, especially (with) our patients with Type 2 diabetes. Having said all that, it's still extremely promising.”

Dr. Russell said that the more severe disease in the models adds to the promise of the medication. “These are highly hyperglycemic animals with pretty severe neuropathy,” he said. “So if you can actually prevent that neuropathy from developing in these animals, that means theoretically in humans the therapy may be more likely to be effective.”

©2011 American Academy of Neurology

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