Valproic acid – The phoenix drug arises again

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.

a)        GABA

I introduced GABA in the blog entry GABA, beta-alanine, carnosine, homocarnosine and gabapentin and have mentioned it in a number of others. GABA “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)” 

Discussions of the GABA-promoting and the HDACinhibiting properties of valproic acid are given in the July 2010 publication Molecular and Therapeutic Potential and Toxicity of Valproic Acid.  “In the human brain, VPA alters the activity of the neurotransmitter Gamma Amino Butyrate (GABA) by potentialising the inhibitory activity of GABA through several mechanisms, including inhibition of GABA degradation, inhibition of GABA Transaminobutyratre (ABAT), increased GABA synthesis, and decreased turnover [5]. Moreover, VPA attenuates N-Methyl-D-Aspartate-mediated excitation [6, 7] and blocks Na+ channels, Ca2+ channels (voltage-dependent L type CACNA1 type C, D, N, and F), and voltage-gated K+ channels (SCN) [8].” 

b)        HDAC inhibition

The blog entry Histone acetylase and deacetylase inhibitors provides an introduction to what histone deacetylase inhibitors (HDAC inhibitors) basically are, how they work and why they are relevant. Basically a HDAC inhibitor keeps a histone, a spindle around which DNA is wrapped, acetylated – which is in an unfolded state that allows relatively unimpeded gene activation.  Inhibition of HDAC promotes decondensed chromatin formation, thereby promoting the expression of genes and consequently modulating processes such as cell growth, differentiation and apoptosis(ref)(ref).  I also touch on the relationship of HDAC inhibition to aging in that blog entry.  Certain substances I have featured in recent blog posts, curcumin in particular(ref), are also powerful HDAC inhibitors, (ref)(ref).

“VPA, as well as other HDAC inhibitors (HDACi), is able to alter expression of many genes. Corresponding proteins were described to play important roles in cellular activity and could influence several important pathways such as cell cycle control, differentiation, DNA repair, and apoptosis [1619].  — VPA specifically targets 2 of the 4 classes of HDACs: class I, subclasses Ia and Ib, and class II, subclass IIa. Within subclass IIa, HDAC9 is an exception to this modulation, being activated by VPA, which is also true for HDAC11 [20]. HDAC 6, 8, and 10 are not modulated. It is interesting to mention that HDAC classes I and II have been reported to be strongly implicated in neuronal function, which could partially explain the action of VPA in neural pathologies(ref).”   

c)         HSP70

The 2009 paper 2009 Valproic acid induces functional heat-shock protein 70 via Class I histone deacetylase inhibition in cortical neurons: a potential role of Sp1 acetylation relates the actions of valproic acid to our old friend HSP 70, a heat-shock protein involved in hormesis.  “Taken together, the data suggest that the phosphatidylinositol 3-kinase/Akt pathway and Sp1 are likely involved in HSP70 induction by HDAC inhibitors, and induction of HSP70 by VPA in cortical neurons may contribute to its neuroprotective and therapeutic effects.” See the blog entry HSP70 to the rescue.

d) VPA and neural stem cell differentiation

I have introduced the topic of neurogenesis in the in my treatise in the section on the Neurological degeneration theory of aging and in the recent blog entry Neurogenesis, curcumin and longevity. “Increasing research evidence suggests that maintaining a sufficient and consistent rate of neurogenesis in the brain, particularly in the hippocampus, is important for the maintenance of cognitive health. Insufficient or irregular neurogenesis is thought to be a causative factor in bipolar disease and other mood disorders.”  Neurogenesis is also critical as an ongoing process in other nervous tissue such as in the spinal column, and for effective repair of certain spinal cord injuries. 

The capability of VPA to induce neural differentiation has been known for some time, at least for certain cancer cells. The 1996 publication Antitumor activity of sodium valproate in cultures of human neuroblastoma cells concluded “The results indicate that VPA, at non-toxic pharmacological concentrations, arrests the growth, induces differentiation and increases immunogenicity of NB cells through non-toxic mechanisms.”  The 2008 online publication Valproic acid induces differentiation and inhibition of proliferation in neural progenitor cells via the beta-catenin-Ras-ERK-p21Cip/WAF1 pathway describes the mechanism.  “We report here that 1 mM VPA simultaneously induces differentiation and reduces proliferation of basic fibroblast growth factor (bFGF)-treated embryonic day 14 (E14) rat cerebral cortex neural progenitor cells (NPCs). The effects of VPA on the regulation of differentiation and inhibition of proliferation occur via the ERK-p21Cip/WAF1 pathway. — We propose that this mechanism of VPA action may contribute to an explanation of its anti-tumor and neuroprotective effects, as well as elucidate its role in the independent regulation of differentiation and inhibition of proliferation in the cerebral cortex of developing rat embryos.” 

Valproic acid as a cancer treatment 

Valproic acid’s capabilities as a HDAC inhibitor motivate a great deal of the scientific interest in this drug as a potential cancer treatment.  One mechanism involved is explained in the 2006 paper Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase B.  RESULTS: Here, we report that a key determinant for the susceptibility of cancer cells to histone deacetylase inhibitors is their ability to maintain cellular Akt activity in response to the treatment. Also known as protein kinase B, Akt is an essential pro-survival factor in cell proliferation and is often deregulated during tumorigenesis. We show that histone deacetylase inhibitors, such as valproic acid and butyrate, impede Akt1 and Akt2 expression, which leads to Akt deactivation and apoptotic cell death. In addition, valproic acid and butyrate induce apoptosis through the caspase-dependent pathway. The activity of caspase-9 is robustly activated upon valproic acid or butyrate treatment. Constitutively active Akt is able to block the caspase activation and rescues cells from butyrate-induced apoptotic cell death.  – CONCLUSION: Our study demonstrates that although the primary target of histone deacetylase inhibitors is transcription, it is the capacity of cells to maintain cellular survival networks that determines their fate of survival.” 

It should be pointed out that valproic acid may play a special therapeutic role for some cancers since not all HDAC inhibitors produce the same results. The July 2010 paper Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation concludes  Individual histone deacetylase inhibitors had specific effects on cell fate decisions during myeloid development. These data provide novel insights into the effects of histone deacetylase inhibitors on the regulation of normal hematopoiesis, which is of importance when considering utilizing these compounds for the treatment of myeloid malignancies and bone marrow failure syndromes.”Another of the multiple actions of VPA related to  cancers is described in the 2007 publication Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia.  “VPA also downregulated c-Myc levels, and induced apoptosis and myeloid differentiation of primary AML cells, leading to decreased colony-forming ability.  Given the role of c-Myc in leukemogenesis, our study suggests that VPA might be a potential therapeutic agent for AML.”

Here is a selection from the many publications relating to VPA as a potential cancer treatment, in  some cases with selected quotes.  Note that the major interest started less than 10 years ago.

2005 Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate.  “Taken together, our data show that the HDAC-I VPA mediates specific priming of malignant cells for innate immune effector mechanisms. These results suggest the clinical evaluation of HDAC-I in solid tumors such as hepatocellular carcinoma, especially in combination with immunotherapy approaches employing adoptive NK cell transfer.”

2005 Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia.  “We conclude that VPA is clinically useful in low-risk MDS. For patients with high-risk MDS, VPA may be combined with chemotherapy or demethylating drugs.”

2006 Valproic acid induces apoptosis in prostate carcinoma cell lines by activation of multiple death pathwaysOur data indicate that the use of valproic acid may be a suitable therapeutic agent in the control of prostate cancer progression and its action appears particularly relevant in the control of refractory stages of prostate cancer.”

2006 The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia.  “We used VPA in 58 patients with acute myeloid leukemia (AML) who were too old and/or medically unfit to receive intensive chemotherapy.”  The study showed some improvement in the patients involved due to VPA but VPA did not provide a cure. “ CONCLUSIONS: Future trials should combine VPA with chemotherapy or demethylating agents.”

2006 Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95- and TRAIL receptor-mediated apoptosis and chemotherapy   This cell-level study concludes “These findings provide a rationale for the development of VA and Apo2L/TRAIL combination as a novel molecular therapeutic for thoracic cancers.”

2007 Valproic acid for the treatment of myeloid malignancies  “When it was used as monotherapy or in combination with all-trans retinoic acid, which synergizes in vitro, VPA achieved hematologic improvement in a subset of patients. Similar to other inhibitors of histone deacetylases, complete or partial remissions rarely were observed.”

2007 Valproic acid induces p21 and topoisomerase-II (alpha/beta) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines.  This cell-level study is of particular interest because glioblastoma cells are particularly refractory to treatment and the disease is a certain and rapid killer. “CONCLUSION: Our study demonstrates that VPA sensitizes U87, U251, and LN18 cells to the cytotoxic effects of etoposide in vitro by inducing differentiation and up-regulating the expression of p21/WAF1 and both isoforms of topoisomerase-II.”  As pointed out in the recent blog entry, Curcumin, cancer and longevity, curcumin, another HDAC inhibitor, is also toxic to glioblastoma cells.

2008  Valproic acid activates Notch1 signaling and induces apoptosis in medullary thyroid cancer cells. CONCLUSIONS: VPA activates Notch1 signaling in MTC cells and inhibits their growth by inducing apoptosis. As the safety of VPA in human beings is well established, a clinical trial using this drug to treat patients with advanced MTC could be initiated in the near future.”

2010 Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation Shows that more than inhibition of HDAC is involved in anti-cancer activities of valproic acid.  “These results suggest that VPA can modulate the degree of Erk1/2 phosphorylation in a manner unrelated to HDAC inhibition and emphasize that changes in the degree of Erk1/2 phosphorylation are also important for the anti-cancer properties of VPA.”

Research on VPA appears to be accelerating exponentially.  A search in on valproate and cancer revealed 47 new 2010 publications.  I list only a few of these highly selectively for flavor.

2010 Phase I Pharmacokinetic and Pharmacodynamic Evaluation of Combined Valproic Acid/Doxorubicin Treatment in Dogs with Spontaneous Cancer.

2010 Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation.

2010 Enhancement of radiation response in osteosarcoma and rhabdomyosarcoma cell lines by histone deacetylase inhibition.

2010 HDAC inhibitor, valproic acid, induces p53-dependent radiosensitization of colon cancer cells.

2010  Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via down-regulation of the Alzheimer amyloid precursor protein.

2010 A combined pretreatment of 1,25-dihydroxyvitamin D3 and sodium valproate enhances the damaging effect of ionizing radiation on prostate cancer cells.

Valproic acid and Parkinson’s Disease

The 2005 publication Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia  suggests a potential role for VPA in treatment of Parkinson’s Disease.  “Parkinson’s disease is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic (DA) neurons in the substantia nigra. Accumulating evidence supports the notion that neuroinflammation is involved in the pathogenesis of this disease. Valproate (VPA) has long been used for the treatment of seizures and bipolar mood disorder. In vivo and in vitro studies have demonstrated that VPA has neuroprotective and neurotrophic actions. In this study, using primary neuron-glia cultures from rat midbrain, we demonstrated that VPA is a potent neuroprotective agent against lipopolysaccharide (LPS)-induced neurotoxicity. Results showed that pretreatment with 0.6 mM VPA for 48 h robustly attenuated LPS-induced degeneration of dopaminergic neurons as determined by [(3)H] dopamine uptake and counting of the number of TH-ir neurons. The neuroprotective effect of VPA was concentration-dependent and was mediated, at least in part, through a decrease in levels of pro-inflammatory factors released from activated microglia. Specifically, LPS-induced increase in the release of TNFa, NO, and intracellular reactive oxygen species was markedly reduced in cultures pretreated with VPA. These anti-inflammatory effects of VPA were time and concentration-dependent correlated with a decrease in the number of microglia. Thus, our results demonstrate that protracted VPA pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity through a reduction in levels of released pro-inflammatory factors, and further suggest that these anti-inflammatory effects may be contributed by VPA-induced reduction of microglia cell number. Taken together, our study reinforces the view that VPA may have utility in treating Parkinson’s disease.”

The 2006 study Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes reports “Our study identifies astrocyte as a novel target for VPA to induce neurotrophic and neuroprotective actions in rat midbrain and shows a potential new role of cellular interactions between DA neurons and astrocytes. The neurotrophic and neuroprotective effects of VPA also suggest a utility of this drug for treating neurodegenerative disorders including Parkinson’s disease. Moreover, the neurotrophic effects of VPA may contribute to the therapeutic action of this drug in treating bipolar mood disorder that involves a loss of neurons and glia in discrete brain areas.”

The 2007 publication Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity  reports “The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation using rodent primary neuron/glia or enriched glia cultures. — We found that VPA induced apoptosis of microglia cells in a time- and concentration-dependent manner. VPA-treated microglial cells showed typical apoptotic hallmarks including phosphatidylserine externalization, chromatin condensation and DNA fragmentation. — Taken together, our results shed light on a novel mechanism whereby HDACIs induce neuroprotection and underscore the potential utility of HDACIs in preventing inflammation-related neurodegenerative disorders such as Parkinson’s disease.”

The 2008 publication Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons relates:  “Parkinson’s disease (PD) is characterized by the selective and progressive loss of dopaminergic (DA) neurons in the midbrain substantia nigra. Currently, available treatment is unable to alter PD progression. Previously, we demonstrated that valproic acid (VPA), a mood stabilizer, anticonvulsant and histone deacetylase (HDAC) inhibitor, increases the expression of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in astrocytes to protect DA neurons in midbrain neuron-glia cultures. The present study investigated whether these effects are due to HDAC inhibition and histone acetylation. — This study indicates that astrocytes may be a critical neuroprotective mechanism of HDAC inhibitors, revealing a novel target for the treatment of psychiatric and neurodegenerative diseases.” 

The 2009 publication Valproic acid is neuroprotective in the rotenone rat model of Parkinson’s disease: involvement of α-synuclein reports:  “The decrease of the dopaminergic marker tyrosine hydroxylase in substantia nigra and striatum caused by 7 days toxin administration was prevented in VPA-fed rats. VPA treatment also significantly counteracted the death of nigral neurons and the 50% drop of striatal dopamine levels caused by rotenone administration. The PD-marker protein alpha-synuclein decreased, in its native form, in substantia nigra and striatum of rotenone-treated rats, while monoubiquitinated alpha-synuclein increased in the same regions. VPA treatment counteracted both these alpha-synuclein alterations. Furthermore, monoubiquitinated alpha-synuclein increased its localization in nuclei isolated from substantia nigra of rotenone-treated rats, an effect also prevented by VPA treatment.”

More on valproic acid and Alzheimer’s  Disease

The 2010 publication Valproic acid enhances microglial phagocytosis of amyloid-beta(1-42)  reports: “BV-2 cells treated with the neuroactive drug valproic acid (VPA) showed greatly enhanced phagocytic activity for both latex beads and Abeta. VPA also reduced microglial viability by inducing apoptosis, as previously reported. The relevance of these in vitro results to the treatment of AD is unclear but further investigation into the effects of VPA on the clearance of Abeta through enhanced microglial phagocytosis is warranted.”

The 2010 publication Valproic acid stimulates clusterin expression in human astrocytes: Implications for Alzheimer’s disease reports “We have observed earlier that histone deacetylase (HDAC) inhibitors can induce the expression of clusterin in several neuroblastoma and glioma cell lines. Recent studies have revealed that valproic acid, a common and well-tolerated drug for epilepsy and bipolar disorders, is a potent HDAC inhibitor. In this study, we examined whether valproic acid can induce the expression of clusterin in human astrocytes. Our results demonstrated that valproic acid is a potent inducer of clusterin expression and secretion in human astrocytes at the therapeutical concentrations.”

Spinal Muscular Atrophy

The 2009 publication The emerging role of epigenetic modifications and chromatin remodeling in spinal muscular atrophy states: “As the leading genetic cause for infantile death, Spinal Muscular Atrophy (SMA) has been extensively studied since its first description in the early 1890s. Though today much is known about the cause of the disease, a cure or effective treatment is not currently available. Recently the short chain fatty acid valproic acid, a drug used for decades in the management of epilepsy and migraine therapy, has been shown to elevate the levels of the essential survival motor neuron protein in cultured cells. In SMA mice, valproic acid diminished the severity of the disease phenotype. This effect was linked to the ability of the short chain fatty acid to suppress histone deacetylase activity and activate gene transcription. Since then, the study of different histone deacetylase inhibitors and their epigenetic modifying capabilities has been of high interest in an attempt to find potential candidates for effective treatment of SMA.”

Valproic acid and repairing spinal cord injury

The final topic I am going to take up here relates to breaking news reported in August 2010.  According to a Science Daily article, Repairing Spinal Cord Injury With Manipulated Neural Stem Cells, “One of the most common causes of disability in young adults is spinal cord injury. Currently, there is no proven reparative treatment. Hope that neural stem cells (NSCs) might be of benefit to individuals with severe spinal cord injury has now been provided by the work of a team of researchers, led by Kinichi Nakashima, at Nara Institute of Science and Technology, Japan, in a mouse model of this devastating condition. — In the study, mice with severe spinal cord injury were transplanted with NSCs and administered a drug known as valproic acid, which is used in the treatment of epilepsy. The valproic acid promoted the transplanted NSCs to generate nerve cells, rather than other brain cell types, and the combination therapy resulted in impressive restoration of hind limb function. The authors hope that this approach, whereby the fate of transplanted NSCs is manipulated, for example by administration of valproic acid, could be developed as an effective treatment for severe spinal cord injury.”

The e-publication of the aforementioned research dated Sept  1 2010 is Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury.  “The body’s capacity to restore damaged neural networks in the injured CNS is severely limited. Although various treatment regimens can partially alleviate spinal cord injury (SCI), the mechanisms responsible for symptomatic improvement remain elusive. Here, using a mouse model of SCI, we have shown that transplantation of neural stem cells (NSCs) together with administration of valproic acid (VPA), a known antiepileptic and histone deacetylase inhibitor, dramatically enhanced the restoration of hind limb function. VPA treatment promoted the differentiation of transplanted NSCs into neurons rather than glial cells. Transsynaptic anterograde corticospinal tract tracing revealed that transplant-derived neurons reconstructed broken neuronal circuits, and electron microscopic analysis revealed that the transplant-derived neurons both received and sent synaptic connections to endogenous neurons. Ablation of the transplanted cells abolished the recovery of hind limb motor function, confirming that NSC transplantation directly contributed to restored motor function.  These findings raise the possibility that epigenetic status in transplanted NSCs can be manipulated to provide effective treatment for SCI.”  The body of the article contains much interesting discussion, for example” In the present study, we adopted what we believe is a novel approach for the treatment of SCI: manipulation of transplanted NSC fate by an epigenetic reagent. A combined treatment involving NSC transplantation and administration of the HDAC inhibitor VPA led to a marked functional recovery. We will refer below to this dual treatment as the HINT (HDAC inhibitor and NSC transplantation) method. Immunohistochemical analysis revealed that VPA administration promoted the neuronal differentiation of transplanted NSCs. We examined extensively the roles of the neurons responsible for reconstruction of broken neuronal networks using 2 neuronal tracers, immunoelectron microscopy, and 2 cell-ablation methods. These results revealed that transplant-derived neurons received projections from endogenous neurons and that their extended processes made synapses with endogenous neurons in the ventral horn.”

Clinical trials of valproic acid

A search of using the term “valproic acid” retrieves 249 trials worldwide.  The list is worth perusing for it indicates the acute interest of pharmaceutical companies in valproic acid and where bets are being placed.  In general, with exceptions it can be noted that:

·        Most of the trials, including many the completed Phase III trials, relate to the traditional applications of valproic acid such as seizure control and psychiatric applications, and there are many new trials relating to these applications.

·        A number of trials for cancer treatments, usually involving VPA in combination with other substances, are in early phases or just being started up

·        A few trials relate to additional medical conditions beyond those mentioned here, such as autism(ref) and withdrawal from opiates.

·        Some cutting-edge applications such as assisting in spinal cord regeneration as mentioned here are not yet in clinical trials.

The evil side of valproic acid

Remember the magic superstition that valerian was protective but also had capability to do evil?  Well, medication with VPA can also on rare occasions induce dementia and Parkinson’s Disease symptoms as reported in this, this and this publication.  Also VPA has been reported to induce delirium in a demented patient in this publication. 

Wrapping it up

·        Valproic acid is a 128 year-old chemical but initial understanding of its biomolecular and epigenetic properties has only emerged recently and there is probably still a lot to be learned about it.

·        The major properties of valproic acid that make VPA interesting to today’s researchers involve distinctions that did not exist until relatively recently.  They are: a) VPA increases the activity of the neurotransmitter Gamma Amino Butyrate (GABA), b) VPA is a histone deacetylase inhibitor, c) VPA induces the mobilization of heat shock proteins, HSP70 in particular , and d) VPA promotes the directed differentiation of certain stem and progenitor cells.

·        Drug applications of VPA traditionally have been focused on control of epilepsy  and psychiatric disorders but intense research and clinical trials suggest that VPA will soon be included in combined treatments for multiple cancers, Parkinson’s Disease, Alzheimer’s Disease and probably a number of other conditions.  I do not think VPA by itself will cure such diseases but will be embodied in more-powerful treatment regimens.

·        VPA can act as an epigenetic switch for stem cell differentiation fate with possibly important implications for regenerative medicine.———————————————–

*          The legend of the Phoenix has been around for centuries. There are a few variations, but the basic idea is this: The Phoenix is a supernatural creature, living for 1000 years. Once that time is over, it builds its own funeral pyre, and throws itself into the flames. As it dies, it is reborn anew, and rises from the ashes to live another 1000 years. Alternatively, it lays an egg in the burning coals of the fire which hatches into a new Phoenix, and the life cycle repeats(ref).”  In its earliest reincarnation, VPA’s herbal ancestor promoted peaceful sleep.  In its latest reincarnation VPA is an epigenetic modifier necessary for directed stem cell differentiation.  I don’t know how many other cycles of reincarnation it will have.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career, since 2007. I believe I am unique among the researchers and writers in the aging sciences community in one critical respect. That is, I personally practice the anti-aging interventions that I preach and that has kept me healthy, young, active and highly involved at my age, now 93. I am as productive as I was at age 45. I don’t know of anybody else active in that community in my age bracket. In particular, I have focused on the importance of controlling chronic inflammation for healthy aging, and have written a number of articles on that subject in this blog. In 2014, I created a dietary supplement to further this objective. In 2019, two family colleagues and I started up Synergy Bioherbals, a dietary supplement company that is now selling this product. In earlier reincarnations of my career. I was Founding Dean of a graduate school and a full University Professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at and an extensive site of my art at Please note that I have recently changed my mailbox to
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14 Responses to Valproic acid – The phoenix drug arises again

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  10. Yes, now earlier in 2014 I can say research findings on valproic acid continue to roll in. A recent one is at*

    “Valproate reopens critical-period learning of absolute pitch.

    AuthorsGervain J,et al. Show allJournal
    Front Syst Neurosci. 2013 Dec 3;7:102. doi: 10.3389/fnsys.2013.00102.

    Absolute pitch, the ability to identify or produce the pitch of a sound without a reference point, has a critical period, i.e., it can only be acquired early in life. However, research has shown that histone-deacetylase inhibitors (HDAC inhibitors) enable adult mice to establish perceptual preferences that are otherwise impossible to acquire after youth. In humans, we found that adult men who took valproate (VPA) (a HDAC inhibitor) learned to identify pitch significantly better than those taking placebo-evidence that VPA facilitated critical-period learning in the adult human brain. Importantly, this result was not due to a general change in cognitive function, but rather a specific effect on a sensory task associated with a critical-period.”

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