In researching the previous blog post Changing the threshold for neuromuscular fatigue in the young and old, carnosine or beta-alanine supplementation, I discovered a fascinating set of relationships among the substances mentioned in the title of this post and promised to report further on them.  I do that here, requiring a review of some of the basic biochemistry involved.  Although I am not clear of all the implications involved, I flag a few of these in the areas of pain management, synapse development and learning, maintaining mental balance, sleep and mental acuity.   

GABA

GABA (gamma-Aminobutyric acid) “is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.^[1] (ref)”  The operation of GABA is complex.  “In vertebrates, GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane of both pre- and postsynaptic neuronal processes. This binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization. Two general classes of GABA receptor are known: GABA_A in which the receptor is part of a ligand-gated ion channel complex, and GABA_B metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins).  GABA_A receptors are chloride channels, that is, when activated by GABA, they allow the flow of chloride ions across the membrane of the cell (ref).” “GABA_B receptors (GABA_BR) are metabotropic transmembrane receptors for gamma-aminobutyric acid (GABA) that are linked via G-proteins to potassium channels.^[1] These receptors are found in the central and peripheral autonomic nervous system^[2](ref). 

Carnosine, homocarnosine, anserine and beta-alanine

Carnosine and homocarnosine are closely related dipeptide substances, both found in substantial quantities in the mammalian brain and muscles, and they are similar also to anserine found in bird muscles and brains as well as humans.  L-Carnosine is a dipeptide composed of the two amino acids L-histidine and beta-alanine.  And Homocarnosine is a dipeptide composed of the amino acids L-histidine and GABA.  The chemical structures of the two substances are remarkably similar; you can see them diagrammed here.  (Unfortunately, the way this blog software is set up it is hard for me to include diagrams here).  This little article L-Carnosine and Related Histamine-Derived Molecules comments further on the three substances. “Carnosine and homocarnosine are both produced by the same ATP-driven enzyme, carnosine synthetase, and both molecules exhibit very similar properties. The concentration of homocarnosine in the human brain, however, is about 100 times that of carnosine. It is manufactured by glial cells (oligodendrocytes) except in the olfactory bulb, where it is synthesized by neurons. The highest brain homocarnosine concentrations are found in the substantia nigra, dentate gyrus and olfactory bulb as well as in the cerebrospinal fluid.”

So, going back to the discussion of the previous blog entry, Changing the threshold for neuromuscular fatigue in the young and old, carnosine or beta-alanine supplementation, chemically, beta-alanine is one of the dipeptide components of l-carnosine, the wonderful stuff discussed in the blog entry The curious case of l-carnosine.  Homocarnosine, on the other hand, molecularly substitutes GABA for beta-alanine. 

The three dipeptides Carnosine, homocarnosine, and anserine, have a number of biological properties in common.  All appear to be antioxidants(ref).  All three are protective against peroxyl radical-mediated Cu,Zn-superoxide dismutase modification(ref).  Both carnosine and homocarnosine can detoxify the highly reactive aldehyde acrolein(ref).  Of particular note, all three are inhibitors of GABA metabolism.  That is, they lead to higher levels of GABA in the brain.  This was pointed out in a 1978 publication Homocarnosine, carnosine and anserine on uptake and metabolism of GABA in different subcellular fractions of rat brain.  “L-Carnosine, L-homocarnosine and L-anserine are inhibitors of GABA metabolism. They show differential action on GABA-transaminase from synaptosomes compared to the extrasynaptosomal enzyme.” A 2004 publication also identifies beta-alanine as a GABA uptake inhibitor. 

Much of the research literature on these substances was published prior to 2000. The more-recent literature has since been scanty and scattered as indicated in the 2005 title Carnosine and homocarnosine, the forgotten, enigmatic peptides of the brain.  

Carnosine and homocarnosine are degraded in the body by carnosinase, “An enzyme that hydrolyzes carnosine (amino-acyl-l-histidine) and other dipeptides containing l-histidine into their constituent amino acids(ref).”  Activity of carnosinase tends to increase with age, leading to lower levels of carnosine in older people, however a very recent publication suggests that the presence of homocarnosine tends to inhibit the degradation of carnosine by carnosinase.  “Activity of carnosinase (CN1), the only dipeptidase with substrate specificity for carnosine or homocarnosine, varies greatly between individuals but increases clearly and significantly with age. — Further, CN1 activity was dose dependently inhibited by homocarnosine. — Homocarnosine inhibits carnosine degradation and high homocarnosine concentrations in cerebrospinal fluid (CSF) may explain the lower carnosine degradation in CSF compared to serum. Because CN1 is implicated in the susceptibility for diabetic nephropathy (DN), our findings may have clinical implications for the treatment of diabetic patients with a high risk to develop DN. Homocarnosine treatment can be expected to reduce CN1 activity toward carnosine, resulting in higher carnosine levels.”

Further background information on carnosine, homocarnosine, anserine and other related nerve and muscle histidine can be found in the online monograph Carnosine and Oxidative Stress in Cells and Tissues. This monograph also describes several pathways through which these substances can be created as metabolic products of each other.

A few of the key points for the purpose of this discussion are:

·        While carnosine can play key health and longevity-supporting roles, it or beta-alanine are far from the only games in town.  Carnosine acts in synergy with homocarnosine and its levels are controlled by carnosinase. 

·        Although exogenous supplementation is possible with one or several of these dipeptides, they are created and broken down in the body in complex ways.  Homocarnosine can be formed when GABA replaces the beta-alanine component in carnosine.  It appears that carnosine and beta-alanine release is stimulated by glutamatergic receptors, at least in cultured rat oligodendrocytes(ref).  

·        Supplementation with carnosine and/or beta-alanine may be valuable for athletes and older people as described in the blog entry Changing the threshold for neuromuscular fatigue in the young and old, carnosine or beta-alanine supplementation.

·        Carnosine, beta-alanine and homocarnosine increase levels of GABA. 

Gabapentin

I have discussed the drug gabapentin in the blog entry Spinal cord injury pain – a personal story and a new paradigm. As pointed out there it has been both a very popular as well as controversial drug used as an antic-convulsant, for control of neuropathic pain and, off-label, for a number of other psychiatric and medical conditions.  Gabapentin, like carnosine, beta-alanine and homocarnosine, is a GABA agonist that increases GABA levels in the brain(ref)(ref).  Further, gabapentin increases brain levels of homocarnosine(ref)(ref).  The studies cited were on patients or on tissues from patients prone to seizures, but I would wager that at least some increases in GABA and homocarnosine levels due to taking gabapentin would apply in general.

In my blog entry on neuropathic pain, I highlighted the possible role of gabapentin in quieting pathological pain due to over-excited microglia.  A July 2009 e-publication suggests that carnosine and N-acetyl carnosine might possibly be able to accomplish a similar result.  “Chronic inflammation and oxidative stress have been implicated in the pathogenesis of neurodegenerative diseases. A growing body of research focuses on the role of microglia, the primary immune cells in the brain, in modulating brain inflammation and oxidative stress. One of the most abundant antioxidants in the brain, particularly in glia, is the dipeptide carnosine, beta-alanyl-L-histidine. — The aim of the present study was to examine the role of carnosine and N-acetyl carnosine in the regulation of lipopolysaccharide (LPS)-induced microglial inflammation and oxidative damage. –. The data shows that both carnosine and N-acetyl carnosine significantly attenuated the LPS-induced nitric oxide synthesis and the expression of inducible nitric oxide synthase by 60% and 70%, respectively.  — we demonstrated a direct interaction of N-acetyl carnosine with nitric oxide. LPS-induced TNFalpha secretion and carbonyl formation were also significantly attenuated by both compounds. N-acetyl carnosine was more potent than carnosine in inhibiting the release of the inflammatory and oxidative stress mediators. These observations suggest the presence of a novel regulatory pathway through which carnosine and N-acetyl carnosine inhibit the synthesis of microglial inflammatory and oxidative stress mediators, and thus may prove to play a role in brain inflammation.”

Having been on gabapentin for three months now has contributed to vanishing my neuropathic pain due to a spinal injury and keeps me sleeping soundly.  See my blog entry Spinal cord injury pain – a personal story and a new paradigm. 

However, there are a few things I don’t like about gabapentin, one being that it often leaves me sleepy in the mornings making it difficult to concentrate. More seriously, I recently discovered something that bothers me a lot: gabapentin inhibits neuron synapse formation and therefore probably impairs new learning.  This was reported in an October 2009 study Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. “We have previously identified thrombospondin as an astrocyte-secreted protein that promotes central nervous system (CNS) synaptogenesis. Here, we identify the neuronal thrombospondin receptor involved in CNS synapse formation as alpha2delta-1, the receptor for the anti-epileptic and analgesic drug gabapentin.“  As explained in the LA Times Booster Shots: “Stanford University researchers examined the interaction between neurons and brain cells called astrocytes. Previous studies showed that a protein that astrocytes secrete, thrombospondin, is critical to the formation of the brain’s circuitry. In the study, researchers found that thrombospondin binds to a receptor, called alpha2delta-1, on the outer membrane of neurons. In a study in mice, they showed that the neurons that lacked alpha2delta-1 could not form synapses in response to the presence of thrombospondin. — Alpha2delta-1 is the receptor for gabapentin. That has been known, although scientists did not understand how gabapentin worked. But the new research revealed that when gabapentin was given to mice, it prevented thrombospondin from binding to the receptor, thus stopping the synapse formation.  While gabapentin, which is sold under the trade name Neurontin, does not dissolve pre-existing synapses, it prevents the formation of new ones. That’s why the medication may be dangerous if given to pregnant women or young children, the authors said. The majority of the brain’s synapses are formed in uteri and early childhood.”  We now know that synapse formation goes on throughout life, and I don’t like the idea of it being stopped in me. 

Some of the questions I am left with are:

·        Is seizure control associated with taking gabapentin due to higher levels of brain homocarnosine or GABA, or due to some other effect of the drug?

·        Can l-carnosine or N-acetyl carnosine achieve some of the pain control and other benefits attributed to gabapentin?

·        What if any of the general health benefits of supplementation by l-carnosine are also achieved by supplementation with beta-alanine, by taking gabapentin?  Is gabapentin a “longevity drug?”

·        What are the actual implications on adult learning of gabapentin inhibiting new synapse formation?

·        What are the differential effects of supplementation with l-carnosine, supplementation with beta-alanine, supplementation with GABA or taking the drug gabapentin on brain neurons, in CNS glial cells and in muscle tissues? 

My current personal plans are 1. to stay on 500mg of l-carnosine twice daily, 2.   To phase off of gabapentin as soon as possible consistent with my neuropathic pain not returning; pursuant to this,I have just phased down from 900mg a day to 600mg, and 3. Of course to keep alert to any new research developments that might affect these decisions.