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Review
, 12 (10), 1728-41

GCH1, BH4 and Pain

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Review

GCH1, BH4 and Pain

Alban Latremoliere et al. Curr Pharm Biotechnol.

Abstract

Understanding and consequently treating neuropathic pain effectively is a challenge for modern medicine, as unlike inflammation, which can be controlled relatively well, chronic pain due to nerve injury is refractory to most current therapeutics. Here we define a target pathway for a new class of analgesics, tetrahydrobiopterin (BH4) synthesis and metabolism. BH4 is an essential co-factor in the synthesis of serotonin, dopamine, epinephrine, norepinephrine and nitric oxide and as a result, its availability influences many systems, including neurons. Following peripheral nerve damage, levels of BH4 are dramatically increased in sensory neurons, consequently this has a profound effect on the physiology of these cells, causing increased activity and pain hypersensitivity. These changes are principally due to the upregulation of the rate limiting enzyme for BH4 synthesis GTP Cyclohydrolase 1 (GCH1). A GCH1 pain-protective haplotype which decreases pain levels in a variety of settings, by reducing the levels of endogenous activation of this enzyme, has been characterized in humans. Here we define the control of BH4 homeostasis and discuss the consequences of large perturbations within this system, both negatively via genetic mutations and after pathological increases in the production of this cofactor that result in chronic pain. We explain the nature of the GCH1 reduced-function haplotype and set out the potential for a ' BH4 blocking' drug as a novel analgesic.

Figures

Fig. 1
Fig. 1
Tetrahydrobiopterin (BH4) is an essential cofactor all three hydroxylases and the three NOS isoforms. The metabolism of phenylalanine and the synthesis of serotonin, dopamine, epinephrine, norepinephrine and NO, are reliant on adequate cellular levels of BH4.
Fig. 2
Fig. 2
Intracellular levels of BH4 depend on three production conduits the de novo synthesis pathway, the recycling pathway and the salvage pathway. BH4 biosynthesis is mediated through the de novo pathway which can be modulated by numerous inflammatory signals, notably through direct regulation of the rate-limiting enzyme GCH1. The recycling pathway allows the recreation of BH4 from the BH2 dispensed by the hydroxylases and is essential to maintain the proper ratio of BH4/BH2 levels. Precise physiological roles for the salvage pathway are not fully characterized, but it acts to keep BH4 levels stable in a similar way to the recycling pathway. Known mutations for key enzymes of the metabolism of BH4 are indicated by an asterisk.
Fig. 3
Fig. 3
The production of BH4 within the DRG plays a critical role in pain signaling. In basal states (A), the de novo synthesis pathway exhibits weak activity and BH4 levels are relatively low but physiologically normal. Here the recycling pathway plays an important role in maintaining adequate levels of BH4. After peripheral nerve injury (B), there is a major upregulation of GCH1 mRNA, protein and consequent enzyme activity and an increase in SPR and QDPR levels but to a lesser extent, which results in very high levels of BH4. In chronic inflammatory states (C), the protein levels of these enzymes are not increased, but there is nonetheless an overproduction of BH4 in the DRG caused by an increase of enzyme activity. Therapeutic strategies that block the de novo synthesis pathway but not the recycling pathway (D) in the peripheral nervous system should allow a reduction of BH4 to non-pathological levels.
Fig. 4
Fig. 4
Possible interactions between BH4 and NOS with TRPV1 and TRPA1. After peripheral nerve injury (A) there is a concomitant upregulation of GCH1 and nNOS. This leads to an increased production of BH4 which binds nNOS, thereby increasing the affinity of the enzyme for L-Arginine (B), resulting in increased production of NO (C). NO sensitizes TRPV1 and TRPA1 channels, explaining how BH4 causes a calcium entry into the neuron (D). Accordingly BH4 application in vivo causes heat hypersensitivity (through TRPV1) and increased pain behavior elicited by formalin (a TRPA1 agonist). Inhibition of GCH1 by DAHP reduces both NO production and pain responses (A) and inhibition of NOS by L-NAME reduces pain behaviors and BH4-mediated Ca2+-influx (C and D).
Fig. 5
Fig. 5
Therapeutic window of inhibiting BH4 synthesis. Following nerve injury neuronal BH4 levels are pushed beyond a threshold which causes chronic pain hypersensitivity therefore blocking GCH1 or BH4 synthesis allows a reduction of BH4 levels below pathological pain levels. If the drug is delivered systemically it will likely tonically inhibit other BH4 synthesis systems within peripheral tissues. The existence of the homozygous carriers of the GCH1 haploytype with no clear deleterious phenotype suggests there is latitude in most members of the population for a reasonable reduction with few, if any pathological side effects. Further, with the addition of certain dietary supplements chronic BH4 deficiency patients suffer few side effects, allowing even stronger suppression if the de novo synthesis cascade is inhibited in the presence of BH4 and neurotransmitter pro-drugs. Blue arrowhead represents onset of drug delivery.

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