Saturday, 24 August 2013

Valproic Acid

Valproic acid and its salts (e.g. sodium valproate [EPILIM]) are quite fascinating drugs when you get down to it. They're chemically quite simple (valproic acid's IUPAC name for those of you that understand what this means is just 2-propylpentanoic acid) were originally synthesised from a compound with a very humble source: the Valerian plant (this is because the Valerian contains valeric acid amongst hundreds of other compounds and valeric acid is also known as pentanoic acid which is quite similar to valproic acid). Valproic acid is also fascinating in that it has so many medical uses including:1
  • as an antimanic (a drug that treats the manic states often seen in patients with bipolar disorder and related psychiatric disorders)
  • as a mood stabiliser in the long-term treatment of bipolar disorder (unfortunately, however, it appears to have limited efficacy in preventing future depressive episodes in patients with bipolar disorder)
  • As an adjunctive (add-on) treatment to antipsychotic therapy in patients treatment-resistant schizophrenia2 and in the treatment of agitation in patients with schizophrenia3
  • Anticonvulsant (anti-seizure medication; this is, in fact, valproic acid's chief medical use. The great thing about valproic acid too is that it works against a broad spectrum of different seizure types. See in epileptic seizures can be divided into various different subtypes according to the parts of the brain that are affected and the symptoms of the seizure and valproic acid appears to work against all types of seizures which is not always the case with anticonvulsants)
  • As an anticancer agent (this use has only become apparent recently and isn't very well studied yet but in theory it definitely should have anticancer activity)4
  • In the prevention of migraines 
  • As an analgesic (painkiller) in patients with neuropathic (nerve injury-related) pain (ironically one type of neuropathic pain it has been tested in is neuropathic pain due to cancer and in this clinical trial it was found effective)
  • The treatment of hallucinations associated with alcohol abuse

It has also been tested as an adjunct (add-on treatment) in the treatment of HIV but in this indication it has been found to be ineffective.5

The mechanism by which valproic acid works these almost majestic effects is not entirely known but, as always, we do have our theories. Its anticonvulsant effects are believed to be mediated by its ability to do the following:
  • Block voltage-dependent sodium channels (in brain and other electrically excitable cells a message is propelled through the cell by means of ions like sodium ions. These sodium channels like other ion channels allows a particular ion [like sodium] into and out of the cell; ions are atoms that have either lost or gained an electron(s))6
  • Inhibit the activity of the enzyme GABA-T which catalyses the breakdown of the neurotransmitter, gamma-aminobutyric acid (GABA). This allows GABA levels in the brain and other tissues to rise and since seizures are due to pathological (usually pathologically excessive) electrical activity in the brain and GABA depresses neuronal [electrically-signalling cells of the brain, spinal cord and nerves] activity, this rise in GABA levels can reduce this pathologically excessive activity.7
  • Potentiating the activity of the enzyme glutamic acid decarboxylase (GAD) – an enzyme that catalyses the synthesis of GABA8

Its antimanic, anticancer and potentially its analgesic effects are probably, at least in part, due to its ability to inhibit the enzyme Histone Deacetylase (HDAC). Histone deacetylase enzymes catalyse the deacetylation of histones – proteins that package and order DNA in the nuclei (centre, almost like the "brain" of the cell) of cells and plays a key role in gene expression (i.e. the generation of proteins like receptors and enzymes from genes). By doing this HDAC inhibitors like valproic acid lead to a significant increase in the expression of certain genes and a reduction in the expression of others. In support of the role of HDAC inhibition in the antimanic effects of valproic acid the other HDAC inhibitor, butyric acid (which, interestingly, is something naturally found in our intestines as a by-product of the bacteria in our intestines metabolising dietary fibre), has been found to be efficacious in an animal model of mania.9 HDAC’s role in cancer cell proliferation (spread), differentiation, etc. is well established as is supported by the fact that the HDAC inhibitor, vorinostat, is Food and Drug Administration (FDA; the US Gov.’s regulatory administration on drugs and food) approved for certain types of cancer.

One protein that is upregulated (i.e. its gene expression is increased by valproic acid) by HDAC inhibitors that may be, in part, responsible for the antimanic and analgesic effects of valproic acid is the metabotropic glutamate receptor 2 (mGluR2).10,11 mGluR2 in turn regulates the release of the neurotransmitter glutamate in various brain and spinal cord areas including those involved in emotional processing and the perception of pain.12 It is also conceivable that mGluR2 receptors may play a role in the anticonvulsant effects of valproic acid since excess glutamatergic activity is implicated in epilepsy. Something that is often predictive of antimanic activity in animal models is antipsychotic activity (which in turn is determined in various different animal models of schizophrenia) and mGluR2 agonists (activators) and potentiators are known to possess significant antipsychotic activity, in fact, one mGluR2/3 receptor agonist (pomaglumetad methionil) was in clinical trials until recently as a potential treatment for schizophrenia. Unfortunately this drug failed phase III (the final phase of clinical testing prior to the approval of the drug) clinical testing despite displaying antipsychotic activity in phase II clinical trials. Another change in gene expression that might be involved in the antimanic effects of valproic acid is that of the brain-derived neurotrophic factor (BDNF) – a protein involved in the protection, reproduction and repair of neurons.13,14 It is also possible that the antimanic effects of valproic acid may be due to its inhibitory effects on glycogen synthase kinase 3β (GSK-3β) expression, which is supported by the fact that the antimanic agent, lithium, also inhibits GSK-3β, albeit via a different mechanism.15

How it works on cancer is very complex considering how many different genes are upregulated in cancer cells relative to their non-cancerous counterparts. The following genes are a few that may play a role in the anticancer effects of valproic acid and its salts:
  • Cyclin D216
  • Amyloid precursor protein17
  • Glycogen synthase kinase 3β (GSK-3β)15

Since the amyloid precursor protein is also involved in the pathogenesis (disease process) of Alzheimer’s disease it may be helpful there.18

However don't get me wrong valproic acid and its salts are definitely not very benign (i.e. has a limited potential to do harm) drugs and some of their side effects can leave one with permanent organ injuries and/or death. Potential life-threatening/debilitating side effects according to Micromedex includes:1
  • Hyperammonaemia (elevated blood levels of ammonia) – which can lead to permanent or temporary brain injury and coma 
  • Liver failure
  • Pancreatitis (inflammation of the pancreas)
  • Thrombocyotpaenia (reduction in the amount of platelets in your blood leading to an increased tendency to bleed) 
  • Palpitations (abnormally rapid, irregular or strong heart beat) 
  • Immune hypersensitivity reaction (a severe allergic reaction to the drug) 
  • Permanent Deafness 
  • Pleural effusion (a build-up of fluid around the lungs)

It has a number of less severe, common side effects but there’s so many that I deem it too tedious to write it out here.


Reference List:

  1. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Aug 24]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  2. Suzuki T, Uchida H, Takeuchi H, Nakajima S, Nomura K, Tanabe A, et al. Augmentation of atypical antipsychotics with valproic acid. An open-label study for most difficult patients with schizophrenia. Human Psychopharmacology: Clinical and Experimental [Internet]. 2009 [cited 2013 Aug 24];24(8):628–38. Available from: http://onlinelibrary.wiley.com/doi/10.1002/hup.1073/abstract
  3. Yoshimura R, Shinkai K, Ueda N, Nakamura J. Valproic Acid improves Psychotic Agitation without Influencing Plasma Risperidone Levels in Schizophrenic Patients. Pharmacopsychiatry [Internet]. 2007 Jan [cited 2013 Aug 24];40(1):9–13. Available from: https://www.thieme-connect.com/DOI/DOI?10.1055/s-2007-958521
  4. Michaelis M, Doerr H, Cinatl Jr. J. Valproic Acid As Anti-Cancer Drug. Current Pharmaceutical Design [Internet]. 2007 Nov 1 [cited 2013 Aug 24];13(33):3378–93. Available from: http://www.eurekaselect.com/60121/article
  5. Routy J, Tremblay C, Angel J, Trottier B, Rouleau D, Baril J, et al. Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study. HIV Medicine [Internet]. 2012 [cited 2013 Aug 24];13(5):291–6. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1468-1293.2011.00975.x/abstract
  6. Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. , Published online: 15 August 2002; | doi:101038/sj.mp4001087 [Internet]. 2002 Aug 15 [cited 2013 Aug 24];7(7). Available from: http://www.nature.com/mp/journal/v7/n7/full/4001087a.html
  7. Johannessen CU. Mechanisms of action of valproate: a commentatory. Neurochemistry International [Internet]. 2000 Aug 1 [cited 2013 Aug 24];37(2–3):103–10. Available from: http://www.sciencedirect.com/science/article/pii/S0197018600000139
  8. Wikinski SI, Acosta GB, Rubio MC. Valproic acid differs in its in vitro effect on glutamic acid decarboxylase activity in neonatal and adult rat brain. General Pharmacology: The Vascular System [Internet]. 1996 Jun [cited 2013 Aug 24];27(4):635–8. Available from: http://www.sciencedirect.com/science/article/pii/0306362395020926
  9. Steckert AV, Valvassori SS, Varela RB, Mina F, Resende WR, Bavaresco DV, et al. Effects of sodium butyrate on oxidative stress and behavioral changes induced by administration of d-AMPH. Neurochemistry International [Internet]. 2013 Mar [cited 2013 Aug 24];62(4):425–32. Available from: http://www.sciencedirect.com/science/article/pii/S0197018613000405
  10. Chiechio S, Zammataro M, Morales ME, Busceti CL, Drago F, Gereau RW, et al. Epigenetic Modulation of mGlu2 Receptors by Histone Deacetylase Inhibitors in the Treatment of Inflammatory Pain. Mol Pharmacol [Internet]. 2009 May 1 [cited 2013 Aug 24];75(5):1014–20. Available from: http://molpharm.aspetjournals.org/content/75/5/1014.full.pdf
  11. Chiechio S, Zammataro M, Morales ME, Busceti CL, Drago F, Gereau RW, et al. Epigenetic Modulation of mGlu2 Receptors by Histone Deacetylase Inhibitors in the Treatment of Inflammatory Pain. Mol Pharmacol [Internet]. 2009 May 1 [cited 2013 Aug 24];75(5):1014–20. Available from: http://molpharm.aspetjournals.org/content/75/5/1014.full.pdf
  12. Czapinski P, Blaszczyk B, Czuczwar S. Mechanisms of Action of Antiepileptic Drugs. Current Topics in Medicinal Chemistry [Internet]. 2005 Jan 1 [cited 2013 Aug 24];5(1):3–14. Available from: http://www.eurekaselect.com/79696/article
  13. Grande I, Fries GR, Kunz M, Kapczinski F. The Role of BDNF as a Mediator of Neuroplasticity in Bipolar Disorder. Psychiatry Investig [Internet]. 2010 Dec [cited 2013 Aug 24];7(4):243–50. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022310/
  14. Yasuda S, Liang M-H, Marinova Z, Yahyavi A, Chuang D-M. The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry [Internet]. 2007 Oct 9 [cited 2013 Aug 24];14(1):51–9. Available from: http://www.nature.com/mp/journal/v14/n1/full/4002099a.html
  15. De Sarno P, Li X, Jope RS. Regulation of Akt and glycogen synthase kinase-3β phosphorylation by sodium valproate and lithium. Neuropharmacology [Internet]. 2002 Dec [cited 2013 Aug 24];43(7):1158–64. Available from: http://www.sciencedirect.com/science/article/pii/S0028390802002150
  16. Venkataramani V, Rossner C, Iffland L, Schweyer S, Tamboli IY, Walter J, et al. Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein. J Biol Chem [Internet]. 2010 Apr 2 [cited 2013 Aug 24];285(14):10678–89. Available from: http://www.jbc.org/content/285/14/10678
  17. Venkataramani V, Rossner C, Iffland L, Schweyer S, Tamboli IY, Walter J, et al. Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein. J Biol Chem [Internet]. 2010 Apr 2 [cited 2013 Aug 24];285(14):10678–89. Available from: http://www.jbc.org/content/285/14/10678
  18. Zhang X-Z, Li X-J, Zhang H-Y. Valproic acid as a promising agent to combat Alzheimer’s disease. Brain Research Bulletin [Internet]. 2010 Jan 15 [cited 2013 Aug 24];81(1):3–6. Available from: http://www.sciencedirect.com/science/article/pii/S0361923009002779

Wednesday, 21 August 2013

D-cycloserine -- An Old Drug Getting A New Life

D-cycloserine is a drug that was once frequently used in the treatment of tuberculosis, nowadays it is less frequently used, probably, in part, due to how rare tuberculosis is nowadays in developed countries like Australia. Nowadays D-cycloserine is generating some interest as a potential treatment for certain psychiatric disorders such as major depressive disorder (MDD) and schizophrenia.1,2 This is because D-cycloserine, much like the non-cyclic form of this amino acid, D-serine, (the related [sort of a mirror image of D-serine] amino acid, L-serine, which is also what the body synthesises D-serine from, is found in animal and vegetable proteins) has been found to bind to the so called glycine site on the NMDA glutamate receptor. The NMDA receptor is one of the receptors for the very important amino acid neurotransmitter, glutamate (also known as glutamic acid). The NMDA receptor primarily serves as an excitatory receptor, that is, it increases the activity of the cells on which it is expressed.

This receptor has been implicated in several of the major psychiatric disorders that have plagued our society for generations such as schizophrenia, bipolar disorder, major depressive disorder and anxiety disorders. In order to be activated, however, the NMDA receptor requires two events to occur simultaneously: the neurotransmitters, glutamate or aspartate (aspartic acid) must bind to the so called glutamate site on the receptor and the neurotransmitter glycine, or similar amino acid neurotransmitters such as D-alanine or D-serine need to bind to the so called glycine site on the receptor. What's so special about D-cycloserine, however, is that it serves as a partial agonist at the glycine site on the NMDA receptor. This means that when it binds to the glycine site, provided glutamate or aspartate is already bound to the glutamate site, a smaller response is seen than if D-serine, D-alanine or glycine had bound to the same glycine site. Hence because the glycine sites on the NMDA receptor are never completely occupied by the glycine, D-serine and the D-alanine obtained from the diet (after some chemical processing) [this is because there are so many NMDA receptors found in the body that it’s impossible for these neurotransmitters to occupy them all] at lower concentrations of D-cycloserine in the blood it (D-cycloserine) occupies the non-occupied glycine sites on the NMDA receptor and hence leads to an overall increase in the activity of the NMDA receptor. At higher concentrations, however, D-cycloserine competes with glycine, D-serine and D-alanine for the binding with the glycine site on the NMDA receptor and hence it displaces some of these amino acid neurotransmitters and hence since it produces a less full response than these amino acid neurotransmitters  it causes a net reduction in NMDA receptor activity.

The way how this relates to psychiatric illnesses like schizophrenia and major depressive disorder is that it is believed that in schizophrenia the NMDA receptor is underactive and hence by potentiating its activity it is hoped that low doses of D-cycloserine (which translates to low concentrations in the blood when the drug is absorbed by the body) may be of therapeutic benefit in patients with schizophrenia. Whereas in major depressive disorder the NMDA receptor is believed to be overactive and drugs that attenuate its activity have been shown to elicit rapid and robust antidepressant effects and hence it is hoped that high doses of D-cycloserine (or high concentrations) might likewise elicit rapid and robust antidepressant effects without some of the psychotomimetic (psychosis [a state characterised by hallucinations, delusions, etc.]-mimicking) effects of NMDA antagonists (blockers) like ketamine.1,2

Its efficacy in treating schizophrenia seems to be very limited, however, probably because the difference between doses that potentiate the activity of the NMDA receptor and doses that inhibit the activity of the NMDA receptor is rather small and the maximum potentiation of NMDA receptor that D-cycloserine is capable of is significantly less than that of glycine site full agonists (compounds that manage [with the help of glutamate/aspartate binding at the glutamate site] to produce full activation of the NMDA receptor) like glycine and hence it is easy to inadvertently give a patient a dose that overall inhibits NMDA activity hence exacerbating the symptoms of schizophrenia.1 

Whereas in treating major depressive disorder D-cycloserine appears to be rather effective, even in previously treatment-resistant cases probably because it’s been discovered that not only do NMDA antagonists produce antidepressant activity but so do NMDA agonists (activators) like glycine and glutamate.2

There is some evidence in rats to suggest that D-cycloserine might be helpful in the treatment of cocaine addiction.3


Reference List:

  1. Goff DC, Cather C, Gottlieb JD, Evins AE, Walsh J, Raeke L, et al. Once-Weekly D-Cycloserine Effects on Negative Symptoms and Cognition in Schizophrenia: An Exploratory Study. Schizophr Res [Internet]. 2008 Dec [cited 2013 Aug 22];106(2-3):320–7. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628436/
  2. Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, et al. A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression. The International Journal of Neuropsychopharmacology. 2013;16(03):501–6. Available from: http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=8852104
  3. Thanos PK, Bermeo C, Wang G-J, Volkow ND. D-cycloserine facilitates extinction of cocaine self-administration in rats. Synapse [Internet]. 2011 [cited 2013 Aug 22];65(9):938–44. Available from: http://onlinelibrary.wiley.com/doi/10.1002/syn.20922/abstract