Posted on 7. September 2010 by Vincent Giuliano

Note: In March 2013, some studies have shown that Valproic acid can be used to slow the progression of some tumors.

The chemical valproic acid has been around for a very long time. It was first synthesized in 1882 and for a great many years it seemed to be not very useful. However, over its 128 year history valproic acid has periodically risen in importance from the ashes like the phoenix bird* as new properties of it were discovered and new important applications found for it. In 1962 it was found to be a powerful anticonvulsant and it soon evolved to become a favorite mood stabilizer. Currently valproic acid seems to have strong potential applications for treating cancers and Alzheimer’s disease, and for guiding stem cell regeneration of nerves in cases of spinal cord injuries. This blog entry briefly covers the history of valproic acid and its major traditional applications and then focuses on important newfound properties of this substance and potential new applications for it.

History of valproic acid

Valerian (Valeriana officinalis) is a perennial plant of European and Asian origin. Dietary supplements have traditionally been made from its roots and have been used as a sedative for dealing with insomnia(ref). My wife tells me that back in the 60s valerian was often found in hippy cookbooks, and has been thought to have magical powers. “Its magical reputation is Evil and Protective, and it is used to Force Love. It is burned in Black Arts Incense for hexing, but added to Uncrossing Incense to destroy jinxes if burned with a yellow candle(ref).” Magic apart, research in the 1990s suggests that valerian achieves its effects through acting on the GABAA (gamma-aminobutyric acid) receptor, promoting the expression of GABA(ref).

“In conclusion, our data show that the extent of GABAA receptor modulation by Valerian extracts is related to the content of valeric acid(ref).” Valproic acid (also known as valproate and abbreviated VPA) is a synthetic substance, not present in the valerian plant. “Valproic acid (by its official name 2-propylvaleric acid) was first synthesized in 1882 by Burton as an analogue of valeric acid, found naturally in valerian.[1] (ref)” As we shall see, VPA too is a strong modulator of the GABA receptor. Although mostly not known to be evil, it is also strongly protective.
For the first 88 years of its history valproic acid did not seem to be good for very much except as a laboratory solvent. “In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for anti-seizure activity. He found that it prevented pentylenetetrazol-induced convulsions in rodents.[2] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide(ref).3”

By 2005, research showed that “Its pharmacological effects involve a variety of mechanisms, including increased gamma-aminobutyric acid (GABA)-ergic transmission, reduced release and/or effects of excitatory amino acids, blockade of voltage-gated sodium channels and modulation of dopaminergic and serotoninergic transmission(ref).” As described in a 2005 review paper, Valproate, a simple chemical with so much to offer, “Valproate is generally regarded as a first-choice agent for most forms of idiopathic and symptomatic generalized epilepsies.”
Soon after VPA started to be used to control seizures in the late 60s and early 70s, research was initiated on possible use of VPA for treatment of bipolar disorders,. By 1989 VPA’s role in treating psychiatric disorders was becoming well established. The 1989 publication Valproate in psychiatric disorders: literature review and clinical guidelines reported “A growing literature suggests that the anticonvulsant medication valproate may be effective and well tolerated in the acute and prophylactic treatment of some mood and psychotic disorders, particularly the manic phase of bipolar disorder and schizoaffective disorder.

Valproate may sometimes be effective even in those patients who have not responded to conventional somatic therapies.” Approved by the FDA for the treatment of manic or mixed episodes, with or without psychotic features , valproic acid is currently marketed as a mood stabilizer under various trade names such as Depakote and Depakene. “Besides its clinical use as an anticonvulsant and mood-stabilizing drug [9], VPA presents beneficial effects in clinical depression [10], absence seizures [11, 12], tonic-clonic seizures, complex partial seizures [13], juvenile myoclonic epilepsy [14], seizures associated with Lennox-Gastaut syndrome [15], migraine headaches, and schizophrenia(ref).” There are ten different branded valproic acid products sold by ten different pharma companies or their branches worldwide.

Additional potential applications of valproic acid

As time has progressed, one after another potential new medical application of valproic acid has emerged, and that process has been continuing until today. For example a July 2910 report indicates Valproic acid shown to halt vision loss in patients with retinitis pigmentosa. “WORCESTER, MASS. – Researchers at the University of Massachusetts Medical School (UMMS) believe they may have found a new treatment for retinitis pigmentosa (RP), a severe neurodegenerative disease of the retina that ultimately results in blindness.

One of the more common retinal degenerative diseases, RP is caused by the death of photoreceptor cells and affects 1 in 4,000 people in the United States. RP typically manifests in young adulthood as night blindness or a loss of peripheral vision and in many cases progresses to legal blindness by age 40. — In the July 20 online edition of the British Journal of Ophthalmology, Shalesh Kaushal, MD, PhD, chair of ophthalmology and associate professor of ophthalmology and cell biology at UMMS, and his team, describe a potential new therapeutic link between valproic acid and RP, which could have tremendous benefits for patients suffering from the disease. In a retrospective study, valproic acid – approved by the FDA to reduce seizures, treat migraines and manage bipolar disorder – appeared to have an effect in halting vision loss in patients with RP and in many cases resulted in an improved field of vision.

Results from this study, in conjunction with prior in vitro data, suggest valproic acid may be an effective treatment for photoreceptor loss associated with RP. — UMass Medical School will be the coordinating site for a $2.1 million, three-year clinical trial funded by the Foundation Fighting Blindness/National Neurovision Research Institute quantifying the potential of valproic acid as a treatment for RP.” The August 2010 paper in the British Journal of Ophthalmology Therapeutic potential of valproic acid for retinitis pigmentosa concludes “Treatment with VPA (valproic acid)_is suggestive of a therapeutic benefit to patients with RP. A placebo-controlled clinical trial will be necessary to assess the efficacy and safety of VPA for RP rigorously.”
In a quite different dimension, VPA might be very useful for treating Alzheimer’s Disease. The 2008 paper Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer’s disease mouse models relates to another action of the versatile substance. “Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer’s disease (AD).

Amyloid β-protein (Aβ), the central component of neuritic plaques, is derived from β-amyloid precursor protein (APP) after β- and γ-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased Aβ production by inhibiting GSK-3β–mediated γ-secretase cleavage of APP both in vitro and in vivo. VPA treatment significantly reduced neuritic plaque formation and improved memory deficits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory deficits of AD model mice. Our study suggests that VPA may be beneficial in the prevention and treatment of AD.”
The 2010 review article Valproic acid as a promising agent to combat Alzheimer’s disease furthers the advocacy of valproic acid as a treatment for AD, and provides an explanation of its actions that are highly relevant for treatment of AD. “Alzheimer’s disease (AD) is one of the most threatening diseases to the elderly population at present. However, there is no yet efficient therapeutic method to AD. Recently, accumulating evidence indicates that valproic acid (VPA), a widely used mood stabilizer and antiepileptic drug, has neuroprotective potential relevant to AD.

Moreover, VPA can induce neurogenesis of neural progenitor/stem cells both in vitro and in vivo via multiple signaling pathways. Therefore, it is suggested that VPA is a promising agent to combat AD.” The operant word here that I will return to is “neurogenesis,” the birth of new neurons through differentiation of neural progenitor cells.

Molecular biology, genetic and epigenetic properties of VPA

So what is going on with valproic acid? Starting out with a sleep-helping plant extract going on to control of seizures and then on to mood stabilization and to possible control of retinitis pigmentosa and further to possible control of Alzheimer’s Disease – what else can it do? What else it can do as we will see includes possible treatment of Parkinson’s Disease and multiple cancers and assistance in regenerating damaged spinal cords through promoting the proper kind of stem cell differentiation. But first I want to discuss a few of the more newly-discovered biochemical properties of valproic acid that gives it such versatile pluripotency.
The major properties of valproic acid that make it interesting to today’s researchers were not known to exist more than 10 to 30 years ago. They are: a) valproic acid increases the activity of the neurotransmitter Gamma Amino Butyrate (GABA through several mechanisms, b) VPA is a histone deacetylase inhibitor, c) VPA induces the mobilization of heat shock proteins, HSP70 in particular , and d) VPA promotes the selective differentiation of certain stem and progenitor cells.