Chronic stress is debilitating, and conventional treatments have involved prescribing benzodiazepines like Xanax and Valium.
Images
from http://www.webmd.com/drugs/2/drug-9824/xanax-oral/details#images
and
http://www.webmd.com/drugs/2/drug-11116/valium-oral/details#images
The amygdala is important in the processing of memory, making decisions, and interpreting information from your senses into emotions (most notably fear).
The chemistry of anxiety is pretty complicated and is simply presented with its key players, based on the research of Dr. Chen's team:
When a mouse is exposed to 30 minutes of stress-producing confinement, a steroid called corticosterone is produced in the adrenal cortex above the kidneys.
This affects a protein called LMO4 which stands for "LIM domain only 4". A LIM domain is basically a structural framework composed of two zinc ions coordinated to two amino acids, and each zinc is connected to a protein strand.
While zinc stabilizes the protein folding, the 2-amino-acid connector provides a hydrophobic core to the structural domain, and the protein strands at both ends are different enough to provide many places for binding different molecules.
How does corticosterone affect LMO4? Experiments reveal that increasing corticosterone causes a decrease in palmitoylation of LMO4. This is an organic reaction of attaching palmitic acid to cysteine residues of a protein. Doing this increases the hydrophobic nature of a cell's membrane.
Preventing this reaction causes LMO4 to remain inside the nuclei of nerve cells, and this hinders LMO4 from interacting with another important player: PTP1B which stands for protein tyrosine phosphatase and is an enzyme in the hypothalamus.
This enzyme has been studied for its potential in treating obesity and type 2 diabetes but its ability to dephosphorylate tyrosine and cysteine residues may also be important in the anxiety cycle.
In allowing PTP1B to increase in the hypothalamus and enhance dephosphorylation, a metabotropic glutamate receptor called mGluR5 is less able to participate in signalling that would lead to the production of endocannabinoids.
The result is that the mice appear more anxious.
The suggestion proposed by the research team is to control the activity of PTP1B, and one molecule tested so far is trodusquemine and has shown impact on this specific enzyme. More research continues on finding compounds that can target a key component in the anxiety cycle and provide better alternatives to treating chronic stress.
Benzodiazepines are basically fused rings of benzene and diazepine.
Over long term use, benzodiazepines can become problematic by affecting a person's memory and attention span. Plus, their non-specificity in treating that part of the brain causing anxiety makes us wonder if we should look into the chemistry behind it.
Now a team of scientists led by Hsiao-Huei Chen at Ottawa Hospital Research Institute has looked into the neurochemistry of stress in mice and focused on several key players in an elaborate cycle that involves endocannabinoids, hydrophobic molecules that act as signalling compounds to alleviate anxiety.
Anandamide or N-arachidonylethanolamine (AEA). The word ananda comes from the Sanskrit meaning "joy or bliss". Endocannabinoids are produced in the body and interact with the same brain receptors as THC or tetrahydrocannabinol, the active ingredient in marijuana.
As we delve into the neurochemistry of stress, we see there are two principle areas involved: the hypothalamus and the amygdala.
The amygdala is important in the processing of memory, making decisions, and interpreting information from your senses into emotions (most notably fear).
The hypothalamus is important in secreting hormones that control body temperature, hunger, thirst, fatigue, sleep, and circadian rhythms.
The chemistry of anxiety is pretty complicated and is simply presented with its key players, based on the research of Dr. Chen's team:
image by Bryan Derksen (Own work using: BKchem) [Public domain], via Wikimedia Commons
Corticosterone is involved in the regulation of energy, immune reactions, and stress. In people, it is an intermediate in making aldosterone which is a major moderator of sodium and potassium ions.
This affects a protein called LMO4 which stands for "LIM domain only 4". A LIM domain is basically a structural framework composed of two zinc ions coordinated to two amino acids, and each zinc is connected to a protein strand.
image by Bassophile at CC-BY-SA-3.0
(http://creativecommons.org/licenses/by-sa/3.0/)],
via Wikimedia Commons
In this example of a LIM domain, zinc ions are gray; beta sheets are yellow; an alpha helix is red; and the protein strands are green.
While zinc stabilizes the protein folding, the 2-amino-acid connector provides a hydrophobic core to the structural domain, and the protein strands at both ends are different enough to provide many places for binding different molecules.
How does corticosterone affect LMO4? Experiments reveal that increasing corticosterone causes a decrease in palmitoylation of LMO4. This is an organic reaction of attaching palmitic acid to cysteine residues of a protein. Doing this increases the hydrophobic nature of a cell's membrane.
CoA represents coenzyme-A. The reaction is reversible because the product contains a thioester, essentially like an ester but with a sulfur instead of an oxygen atom.
Preventing this reaction causes LMO4 to remain inside the nuclei of nerve cells, and this hinders LMO4 from interacting with another important player: PTP1B which stands for protein tyrosine phosphatase and is an enzyme in the hypothalamus.
image of PTP1B by Emw (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0), via Wikimedia Commons
This enzyme has been studied for its potential in treating obesity and type 2 diabetes but its ability to dephosphorylate tyrosine and cysteine residues may also be important in the anxiety cycle.
PTP1B does the dephosphorylation in 2 steps, and hydrogen bonding helps orient the water molecule long enough to remove the phosphate group from a cysteine residue.
Mechanism from NK Tonks, http://www.ncbi.nlm.nih.gov/pubmed/12829250
In allowing PTP1B to increase in the hypothalamus and enhance dephosphorylation, a metabotropic glutamate receptor called mGluR5 is less able to participate in signalling that would lead to the production of endocannabinoids.
As a metabotropic receptor, mGluR5 indirectly affects ion channels in the post-synaptic neurons in the brain.
The result is that the mice appear more anxious.
Photo
credit: Kuttelvaserova Stuchelova, via
Shutterstock
The suggestion proposed by the research team is to control the activity of PTP1B, and one molecule tested so far is trodusquemine and has shown impact on this specific enzyme. More research continues on finding compounds that can target a key component in the anxiety cycle and provide better alternatives to treating chronic stress.
For more reading:
*"Helping Brains Relieve Anxiety" by Michael Torrice, Chemical & Engineering News, News of the Week, Vol. 93, Issue 10, p 5
*"Chronic Stress Induces Anxiety via an Amygdalar Intracellular Cascade that Impairs Endocannabinoid Signaling" by Z. Qin, X. Zhou, N.R. Pandey, H.A. Vecchiarelli, C.A. Stewart, X. Zhang, D.C. Lagace, J.M. Brunei, J.C. Beique, A.F. Stewart, M.N. Hill, H.H. Chen
*"Coordinated Regulation of Insulin Signaling by the Protein Tyrosine Phosphatases PTP1B and TCPTP" by S. Galic, C. Hauser, B.B. Kahn, F.G. Haj, B.G. Neel, N.K. Tonks, and T. Tiganis
*"Helping Brains Relieve Anxiety" by Michael Torrice, Chemical & Engineering News, News of the Week, Vol. 93, Issue 10, p 5
*"Chronic Stress Induces Anxiety via an Amygdalar Intracellular Cascade that Impairs Endocannabinoid Signaling" by Z. Qin, X. Zhou, N.R. Pandey, H.A. Vecchiarelli, C.A. Stewart, X. Zhang, D.C. Lagace, J.M. Brunei, J.C. Beique, A.F. Stewart, M.N. Hill, H.H. Chen
*"Coordinated Regulation of Insulin Signaling by the Protein Tyrosine Phosphatases PTP1B and TCPTP" by S. Galic, C. Hauser, B.B. Kahn, F.G. Haj, B.G. Neel, N.K. Tonks, and T. Tiganis
