Saturday, January 19, 2013

Protective inhibition, energy generation, and the neuroprotective effects of ATP


Terminology

Axon: the slender part of a neuron that conducts electrical impulses away from the neuron’s cell body.
Autonomic ganglia: a cluster of neurons that provides a junction between the autonomic nerves originating from the brain and spinal cord, with those supplying tissues in the body.
Glial cells: non-neuronal cells that provide support to neurons by, for instance, producing myelin.
Heat shock proteins: “chaperone” proteins that, among their many other roles, help us resist stress (including heat stress).
Purine: a heterocyclic aromatic compound, consisting of a pyrimidine ring and an imidazole ring.  Examples include caffeine, adenosine, AMP, ADP, and ATP.
Protective inhibition: an organism’s response to overwhelming stimuli, manifesting as the cessation of metabolic activities.
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The generation of energy, ATP, is fundamental to the survival of all cells, and so when energy generation declines, for whatever reason, adaptive mechanisms kick in to shut down metabolic activities because otherwise, cells would sustain irrevocable damages and ultimately self-destruct (Jurkowitz, Litsky, Browning, & Hohl, 1998).

Energy problems should be expected to manifest in the neurons most prominently due to their high rates of energy use, but last, due to the importance of the functioning of the so-called “nervous system.”

Nonetheless, when energy problems do manifest, adenosine is permitted to accumulate inside cells, and adenosine in turn exerts an inhibitory effect on the presynaptic release of excitatory neurotransmitters from the peripheral and central arms of the “nervous system.” (This was part an parcel to the concept of “protective inhibition,” put forth by the Russian physiologist and psychologist, Ivan Pavlov, in the 1950s.)

In doing so, however, the development of neurons suffer, like the axons, whose development requires the tonic release and reuptake of ATP to and from the extracellular space.   Adenosine is seen in pathological conditions, at higher-than-normal levels, and by shutting down cellular activities, exerts sedative, anticonvulsant, and neuroprotective effects.  In fact, certain purine derivatives are currently under investigation for use in degenerative conditions of the brain, like Alzheimer’s disease, taking advantage of the trophic effects of purines in the growth and development of neurons and glial cells (Sawmiller, Nguyen, Markov, & Chen, 2012). 

ATP is present in every cell in the body at very low (millimolar) concentrations, wherein it acts as a cardinal adsorbent, per Dr. Gilbert Ling (rest assured this will be discussed at some point in the future), and is released on injury or stimulation.  Thereafter, outside the cell, ATP is rapidly metabolized to ADP, then to AMP, and eventually to adenosine by nucleotidases.

Released by various neurons of the autonomic nervous system, it is now firmly established that ATP functions as a neurotransmitter and has wide-ranging effects in the body.  ATP, for instance, rapidly relaxes intestinal smooth muscles (e.g., in the blood vessels and bladder), and serves as a “fast” transmitter (much like choline, GABA, and glutamate) in the central nervous system and autonomic ganglia.  ATP is also considered an important long-term regulator of the “nervous system” via separate pathways from its role as a “fast” transmitter.

ADP functions as an important signaling molecule in the blood-clotting cascade.  That is, platelets release, from certain secretory vesicles, ADP, and ADP then stimulates platelet aggregation and the release of ADP from other platelets, in a typical positive feedback fashion.  Adenosine in turn inhibits platelet aggregation. 

In addition to being produced by nucleotidases in the extracellular space, adenosine is also found freely in cell's cytoplasm.  In this way adenosine functions as a signal that coordinates metabolic activities with energy availability; so when ATP is not supplied quickly enough, adenosine accumulates intracellularly, and as a protective reflex, adenosine shuts down the cell’s metabolic activities. (Again, we can invoke Pavlov’s concept of “protective inhibition.”) 

The accumulation of adenosine is associated with a myriad of unintended consequences, including asthma, allergies, and chronic obstructive pulmonary disease (Mohsenin & Blackburn, 2006).  Xanthine compounds, such as caffeine, can be supportive in this regard because they are specific antagonists of the adenosine receptors (Townsend, Yim, Gallos, & Emala, 2012).

Carbon monoxide and the generation of reactive oxygen species serve the same purpose of shutting down the cell’s metabolic activities (Zuckerbraun et al., 2007).  In diabetics this results from an excessive oxidation of fats, which ultimately leads to the upregulation of pyruvate kinase–an enzyme that inhibits pyruvate metabolism – inhibiting glucose oxidation and producing a low efficiency of energy generation, with an attendant impairment of tissue and organ functioning (McCormack, Edgell, & Denton, 1982).

Apart from its role as a neurotransmitter, ATP functions as a ligand for membrane-bound potassium channels that in the pancreas, for instance, is required for insulin secretion.  When energy generation is decreased or impaired, like from stimulating uncoupling of energy generation from nutrient processing by the excessive oxidation of fat (discussed here), it’s not hard to imagine some of the consequences that would manifest with regard to the interest of diabetes, one of which includes the impaired secretion of insulin, resulting in poor glucose clearance and apparent diabetes.

Readers of this blog know that stress is ever present, even while asleep (e.g., the heart continues to pump and the brain consolidates memories), and this places continuous energy demands on the body.  This is physiological and not harmful at all.  It’s only when we aren’t able to generate energy sufficiently, like when stress is excessive or prolonged, that we can run into problems.  Herein is the basis for determining the nature of a healthy diet – that is, one that fortifies our resistance to stress.

Sucrose is one such protective dietary factor, and it’s no surprise that animals and humans, under stress, studies have shown, tend to eat more sugary foods.  In particular, sucrose, by increasing the expression of certain heat shock proteins in the brain, is protective against a myriad of environmental insults, and this protective effect only kicks in when great stress is encountered (Kanazawa et al., 2003).  Heat shock proteins provide protection to all parts of the brain, including the hypothalamus, cerebellum, and cerebral cortex, by ameliorating stress itself and by assisting in the repair processes afterwards (Franklin, Krueger-Naug, Clarke, Arrigo, & Currie, 2005).

Recently, a reader asked me to comment on the concept of “autophagy” with interest to the purported benefits of intermittent fasting.  I don’t share the view that most people have on “autophagy”–mostly because the evidence for it in humans is circumstantial. (The benefits seen in worms have yet to be adequately translated to humans.) 

Briefly, “autophagy” refers to the digestion of the least essential parts of cells in order to provide energy in the face of severe nutrient depleted conditions.  While writing this post today, I’ve been thinking more about this process, namely the validity of it for purpose of justifying the benefits of intermittent fasting.

For now, rather than resorting to this extreme practice whose details  (such as how much fasting is needed to not only induce “autophagy” but also, to reap benefits) have yet to be fleshed out, keeping the metabolic rate (and thus thyroid functioning) up, reducing excess body fat, and eating more moderately, over time, should in principle produce the same benefits without the attendant consequences associated with a decrease in energy generation discussed in this post.


References

Franklin, T. B., Krueger-Naug, A. M., Clarke, D. B., Arrigo, A.-P., & Currie, R. W. (2005). The role of heat shock proteins Hsp70 and Hsp27 in cellular protection of the central nervous system. International journal of hyperthermia: the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group, 21(5), 379–92. doi:10.1080/02656730500069955
Jurkowitz, M. S., Litsky, M. L., Browning, M. J., & Hohl, C. M. (1998). Adenosine, inosine, and guanosine protect glial cells during glucose deprivation and mitochondrial inhibition: correlation between protection and ATP preservation. Journal of neurochemistry, 71(2), 535–48. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9681443
Kanazawa, M., Xue, C. Y., Kageyama, H., Suzuki, E., Ito, R., Namba, Y., Osaka, T., et al. (2003). Effects of a high-sucrose diet on body weight, plasma triglycerides, and stress tolerance. Nutrition reviews, 61(5 Pt 2), S27–33. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12828189
McCormack, J. G., Edgell, N. J., & Denton, R. M. (1982). Studies on the interactions of Ca2+ and pyruvate in the regulation of rat heart pyruvate dehydrogenase activity. Effects of starvation and diabetes. The Biochemical journal, 202(2), 419–27. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1158126&tool=pmcentrez&rendertype=abstract
Mohsenin, A., & Blackburn, M. R. (2006). Adenosine signaling in asthma and chronic obstructive pulmonary disease. Current opinion in pulmonary medicine, 12(1), 54–9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16357580
Sawmiller, D. R., Nguyen, H. T., Markov, O., & Chen, M. (2012). High-energy compounds promote physiological processing of Alzheimer’s amyloid-β precursor protein and boost cell survival in culture. Journal of neurochemistry, 123(4), 525–31. doi:10.1111/j.1471-4159.2012.07923.x
Townsend, E. A., Yim, P. D., Gallos, G., & Emala, C. W. (2012). Can we find better bronchodilators to relieve asthma symptoms? Journal of allergy, 2012, 321949. doi:10.1155/2012/321949
Zuckerbraun, B. S., Chin, B. Y., Bilban, M., D’Avila, J. de C., Rao, J., Billiar, T. R., & Otterbein, L. E. (2007). Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 21(4), 1099–106. doi:10.1096/fj.06-6644com