Loud noises kill hair cells

According to coauthor Shaowen Bao, adjunct assistant professor in the Helen Wills Neuroscience Institute at UC Berkeley, tinnitus – pronounced TIN-it-tus or tin-NIGHT-us – is most commonly caused by hearing loss. Sustained loud noises, as from machinery or music, as well as some drugs can damage the hair cells in the inner ear that detect sounds. Because each hair cell is tuned to a different frequency, damaged or lost cells leave a gap in hearing, typically a specific frequency and anything higher in pitch.

Experiments in the past few years have shown that the ringing doesn’t originate in the inner ear, though, but rather in regions of the brain – including the auditory cortex – that receives input from the ear.

Bao’s experiments in rats with induced hearing loss explain why the neurons in the auditory cortex generate these phantom perceptions. They showed that neurons that have lost sensory input from the ear become more excitable and fire spontaneously, primarily because these nerves have “homeostatic” mechanisms to keep their overall firing rate constant no matter what.

“With the loss of hearing, you have phantom sounds,” said Bao, who himself has tinnitus. In this respect, tinnitus resembles phantom limb pain experienced by many amputees,

One treatment strategy, then, is to retrain patients so that these brain cells get new input, which should reduce spontaneous firing. This can be done by enhancing the response to frequencies near the lost frequencies. Experiments over the past 30 years, including important research by Merzenich, have shown that the brain is plastic enough to reorganize in this way when it loses sensory input. When a finger is amputated, for example, the region of the brain receiving input from that finger may start handling input from neighboring fingers.

Bao noted that retraining the ear has been tried before, but with limited success. Most such attempts have taken patients with some residual hearing and trained their ears to be more sensitive to the affected frequencies. This wouldn’t work for patients with profound hearing loss, however.

Most retraining is also based on the assumption that reorganization of the brain – that is, changing how frequencies “map” to regions of the auditory cortex – is a cause of the tinnitus. This is the opposite of Bao’s conclusion.

“We argue that reorganizing the cortical map should be the goal, so that the nerves get some input and stop their tinnitus activity,” he said. “You don’t want to leave these cells without sensory input.”

“We changed our (brain training) strategy from one where we completely avoided the tinnitus domain to one where we directly engage it and try to redifferentiate or reactivate it, and we seem to be seeing improvement,” Merzenich said.

Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L–arginine, a conditionally essential amino acid. ADMA interferes with L-arginine in the production of nitric oxide (NO), a key chemical involved in normal endothelial function and, by extension, cardiovascular health.

Discovery

Patrick Vallance and his London co-workers first noted the interference role for asymmetric dimethylarginine in the early 1990s.^[1] Today biochemical and clinical research continues into the role of ADMA in cardiovascular disease, diabetes mellitus, erectile dysfunction and certain forms of kidney disease.

Synthesis and regulation in the body

Cardiovascular effects have been linked to ADMA

Asymmetric dimethylarginine is created in protein methylation, a common mechanism of post-translational protein modification. This reaction is catalyzed by an enzyme set called S-adenosylmethionine protein N-methyltransferases (protein methylases I and II).^[2] The methyl groups transferred to create ADMA are derived from the methyl group donor S-adenosylmethionine, an intermediate in the metabolism of homocysteine. (Homocysteine is an important blood chemical because it is also a marker of cardiovascular disease). After synthesis, ADMA migrates into the extracellularspace and thence into blood plasma. Asymmetric dimethylarginine is measured using high-performance liquid chromatography.

ADMA concentrations are substantially elevated by native or oxidized LDL cholesterol.^[3] Thus a spiralling effect occurs with high endothelial LDL levels causing greater ADMA values, which in turn inhibit NO production needed to promote vasodilation. The elimination of ADMA occurs through urine excretion and metabolism by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The role of homocysteine as a risk factor for cardiovascular disease is suggested to be mediated by homocysteine down-regulating production of DDAH in the body. Polyphenol antioxidants also play a role in down-regulating homocysteine.

ADMA and suggested lines of therapeutic research

ADMA may play a role in certain forms of kidneydisease

With raised levels of ADMA seemingly to be associated with adverse human health consequences for cardiovascular disease, metabolic diseases, and also a wide range of diseases of the elderly, the possible lowering of ADMA levels may have important therapeutic effects. However, it has yet to be established whether ADMA levels can be manipulated and, more important, if this results in useful clinical benefits.

The association of ADMA with abnormalities of lipid regulation suggested that supplements of free fatty acids might manipulate ADMA levels. However, research has failed to show that these have an effect.^[4][5]

ADMA’s role has been linked with elevated levels of homocysteine.^[6][7][8] Whilst approaches at modifying the latter with oral supplements of folic acid were strongly suggested, studies have shown this fails to give any clinical benefit and suggested that B vitamins might instead increase some cardiovascular risks.^[9][10][11]

Direct alteration of ADMA levels with supplements of L-arginine have been suggested.^[12][13] The hope is that such intervention might not only improve endothelial function but also reduce clinical symptoms of overt cardiovascular disease.^[14][15] However studies show inconsistency in results in a clinical context,^[16] and the recent results with manipulating homocysteine levels warrant extreme care with what clinical outcomes might arise from this approach.

Statins, as well as affecting circulating cholesterol levels, also increase nitric oxide levels and so have a direct effect on blood supply to the heart. Elevated levels of ADMA seems to modify this effect and so may have consequences for patients’ responsiveness to taking statins.^[17]

Connie’s comments: Protein derived from red meat is not healthy to our heart when eaten in great quantities without any fiber from veggies and without the benefit of exercise.

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Dear All,

This 2018, let’s learn new skills and love more.

Have a prosperous and healthy new year!

Connie