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Thoughts on glutamine?
Glutamine is a simple amino acid that has been clinically proven to provide tissue protection under the stress of chemo or radiation therapy as well as after intestinal surgery. Surprisingly, this effect has never been studied to any degree in the nervous system to determine if neurons can be similarly protected from neurodegeneration, as in Alzheimer's disease. Dr. Karl Herrup and colleagues have developed preliminary data to show that this is likely, and they propose a series of experiments both in tissue culture and in mouse models to move this idea as rapidly as possible towards its application in human beings.
The central hypothesis of this study is that glutamine has the potential to become a potent agent in the prevention and treatment of Alzheimer's disease (AD). This innovative concept has strong roots in the clinical and biological literature and is solidly supported by both cell culture and animal studies performed in the laboratory of Dr. Karl Herrup. The experiments are designed to test this idea first in laboratory-grown cells by studying the ability of different glutamine concentrations to block the effects of AD-specific toxins such as the amyloid-beta protein, as well as oxidants like hydrogen peroxide. Based on the results from these studies, the work will be extended into living mice to ask whether oral glutamine can stop the development of Alzheimer's-like pathology in animals that carry genes that promote Alzheimer's disease in humans. The study will then combine glutamine with other agents known to reduce the risk of AD, specifically two common “NSAID” drugs, ibuprofen and naproxen. One of the most innovative aspects of this proposal is its simplicity. Glutamine has a long history of use in internal medicine and oncology, but its protective properties have never been seriously examined with respect to degenerative diseases of the nervous system, either alone or in conjunction with other drugs. With parallel approaches in tissue culture and in live animals, the study is designed to create a strong platform from which to ask whether combinatorial therapies can be developed that would provide the beneficial effects of NSAIDs, but at the lower doses that would be both effective and well tolerated in humans. The successful execution of the study will provide a solid set of observations that could rapidly be advanced to clinical testing, since glutamine is known to be well tolerated and safe.
This gets rather close to the heart of Alzheimer's disease. Glutamine may act as an antioxidant on its own, but more importantly it is one of three compounds that form the brain's master antioxidant--glutathione (the other two are cysteine and glycine). As oxidative stress increase, gluthatione levels decrease and the result is likely Alzheimer's disease.
One phenomenon that has gained a strong foothold as a lead player in Alzheimer’s pathology is ‘oxidative stress’. Oxidative metabolism – the process that yields all cells the energy required for survival – produces highly reactive oxidative byproducts, which if not curtailed wreak absolute havoc on a neuronal cell. To defuse these oxidizing products, the brain cells manufacture antioxidants, which act to police and neutralize these rabble-rousers. The predominant of these brain antioxidants – Glutathione aka GSH– has long been indirectly implicated in Alzheimer’s: from post-mortem brains to cell models of the disease, research has repeatedly offered indirect evidence for depletion of GSH levels in Alzheimer’s disease...
The hippocampi – the brain centres for learning and memory – are one of the earliest regions to be sabotaged by Alzheimer’s pathology. Our data revealed that GSH levels plummet in the hippocampi of patients with Alzheimer’s as well as those with MCI [Mild Cognitive Impairment]. The frontal cortices – brain CEOs responsible for a variety of executive functions – are chronologically affected later in Alzheimer’s. GSH levels mimic this chronology with no changes in the cortices of MCI patients, but significant reduction in those of Alzheimer’s patients. Interestingly, GSH remains unaffected in the cerebellum – a brain region unaffected by Alzheimer’s till late stages. It appears GSH decline is not ubiquitous but rather a region-specific phenomenon that appears to precisely map the progression of Alzheimer’s in our brains.
Unfortunately, glutathione does not enter cells well on its own. Certain bacteria produce glutathione, therefore probiotic supplementation may be of some help.
Another approach is to increase the precursors to glutathione. N-acetylcystine supplementation does not seem to help much as the transporter for cysteine is damaged in Alzheimer's disease.
The main problem in regards to glutamine is that its synthesis from glutamate is inhibited in Alzheimer's disease. The buildup of glutamate is further exacerbated because its own transportation and subsequent disposal are also inhibited. This leads to massive oxidative stress and to the death of neurons.
The neurodegeneration in AD is characterized by synaptic and neuronal loss with plaque and tangle formation. Abnormal expression or processing of growth-associated proteins in the central nervous system may play a role in the process, leading to damage and neurodegeneration. Amyloid precursor protein has been implicated as being important in the pathogenesis of AD. Recently, it has been demonstrated that abnormal processing of amyloid precursor protein may be associated with the deficient functioning of the glutamate transporter system. In fact, a fragment of Beta-amyloid (Abeta), the central constituent of neuritic plaques in AD, inhibited tritium-labeled glutamate uptake in cultured astrocytes. Since reactive oxygen species are mediators of Abeta toxic effects and uptake inhibition by Abeta was prevented by antioxidants, it is conceivable that, among other effects, Abeta produces glutamate transporter oxidation and dysfunction.
The addition of glutamine may be of some value in and of itself but it would likely not lead to increased levels of glutathione in the brain (or not by much). The key to treating Alzheimer's is to find antioxidants that reach the brain in high enough concentrations and are nearly as effective antioxidants as glutathione.
The grant duration was from 2012 to 2016 and the amount was $300,000. Below is a link to the published results. I am not a scientist so I am not good at evaluating the results, but it would have been a lot more interesting if it had been a clinical trial instead of experimenting with mice.
Yes, clinical trial results are preferred over mouse studies. Even a mouse designed to have the genetic mutations that lead to Alzheimer's disease does not develop full Alzheimer's disease.
In Alzheimer's disease, glutamine synthetase (the enzyme that converts glutamate to glutamine) is damaged by tyrosine nitration.
A considerable body of evidence indicates that the activity of glutamine synthetase is decreased in the cerebral cortices of brains affected by Alzheimer's disease...That such dramatic changes occur in the distribution of this critical, and normally stable enzyme, suggests that the glutamate-glutamine cycle is profoundly impaired in Alzheimer's disease. This is significant because impairments of the glutamate-glutamine cycle are known to cause alterations of mood and behaviour, disturbance of sleeping patterns, amnesia, confusion and reduced awareness. Since these behavioural changes are also seen in Alzheimer's disease, it is speculated that they might be attributable to the reduced expression of glutamine synthetase or to impairments of the glutamate-glutamine cycle.
Going slightly further afield: noreadrenaline has been suggested as a root cause of neuropsychological problems in Alzheimer's disease and several other forms of dementia. Noreadrenaline appears to increase glutatmate but not glutamine levels.
The findings suggest that noradrenaline stimulates the rates of glutamine uptake, glutamate synthesis, and CO2 production from glutamine and thus increases energy supply to astrocytes but has no effect on the opposite reaction, i.e., glutamine formation from glutamate, a reaction of importance for neuronal-astrocyte interations.
The behavioral and psychological symptoms of dementia (BPSD) are common serious problems that are a major contributor to caregiver burden. Despite their significance, the underlying neurobiology of these disturbances is still unclear. This review examines the role of norepinephrine (NE) on BPSD, including depression, aggression, agitation and psychosis. A number of lines of evidence suggest that NE dysfunction leading to BPSD may result from increased NE activity and/or hypersensitive adrenoreceptors compensating for loss of NE neurons with progression of Alzheimer's disease (AD). With greater appreciation of the underlying neurobiology of behavioral and psychological symptoms of dementia (BPSD) more effective, rational, targeted pharmacotherapy will hopefully emerge.
Ferulic acid and THC which lower norepinephrine levels appear to help in treating neuropsychiatric problems in Alzheimer's disease (and in the case of ferulic acid at least in Dementia with Lewy Bodies and Frontotemperal lobe dementia).