Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate

Berg, Stacey L.; Serabe, Baruti M.; Aleksic, Aleksander; Bomgaars, Lisa; McGuffey, Leticia; Dauser, Robert C.; Durfee, John; Nuchtern, Jed G.; Blaney, Susan M.

doi:10.1007/s002800000256

Cited by 33 publications

(23 citation statements)

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“…However, a similar trend was found also in our recent open pilot study. 10 Regarding our present data, it may be not by chance that the patient (P4) with the highest mean increase in SMN transcript levels showed also the more obvious improvement in muscle strength and the case with the lowest mean increase (P6 who has taken a 33% reduced dosage) had no change in muscle strength. Further data on the effect of PB on muscle strength will be provided by the ongoing placebo-controlled double-blind clinical trial.…”

Section: Discussionmentioning

confidence: 65%

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Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients

et al. 2004

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Spinal muscular atrophy (SMA) is caused by insufficient levels of survival motor neuron (SMN) protein.Recently, we found that sodium 4-phenylbutyrate (PB), a well-tolerated FDA approved drug, enhances SMN gene expression in vitro. We provide here the first evidence that oral administration of PB (triButyrate s ) significantly increases SMN expression in leukocytes of SMA patients. This finding provides a strong rationale to further investigate the effects of PB as also supported by preliminary clinical data.

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Section: Discussionmentioning

confidence: 65%

“…9 Recently, evidence was given that PB can cross the blood -brain barrier. 10 A drawback to the use of PB is its short-half life (0.8 -1 h). Previous pharmacokinetic studies have shown rapid changes in serum levels of PB in treated subjects with Phenylbutyrate increases SMN expression in vivo C Brahe et al sickle cell disease.…”

Section: Discussionmentioning

confidence: 99%

Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients

et al. 2004

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“…penetrate well into cerebrospinal fluid (Berg et al, 2001); therefore, the findings in this study suggest a great potential role for 4-PBA as a therapeutic agent to restore memory function in AD.…”

Section: Discussionmentioning

confidence: 91%

Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

Ricobaraza

Cuadrado‐Tejedor

Pérez-Mediavilla

et al. 2009

Neuropsychopharmacol

371

265

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Chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Sodium 4-phenylbutyrate (4-PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. In this study, we report that administration of 4-PBA reversed spatial learning and memory deficits in an established mouse model of Alzheimer's disease (AD) without altering b-amyloid burden. We also observed that the phosphorylated form of tau was decreased in the AD mouse brain after 4-PBA treatment, an effect probably due to an increase in the inactive form of the glycogen synthase kinase 3b (GSK3b). Interestingly, we found a dramatic decrease in brain histone acetylation in the transgenic mice that may reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription of synaptic plasticity markers such as the GluR1 subunit of the AMPA receptor, PSD95, and microtubule-associated protein-2. The results suggest that 4-PBA, a drug already approved for clinical use, may provide a novel approach for the treatment of AD.

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“…administration in nonhuman primates. 29 These data raise the possibility that PBA could stimulate SMN expression in motor neurons.…”

Section: Discussionmentioning

confidence: 97%

Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy

et al. 2003

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Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease, characterized by degeneration of the anterior horn cells of the spinal cord. SMA presents with a highly variable phenotype ranging from very severe to mild (type I-III). No cure for SMA is available at present. All forms of SMA are caused by homozygous loss of the functional survival motor neuron (SMN1) gene. However, all patients have one or more copies of the SMN2 gene, nearly identical to SMN1. Both genes encode the SMN protein but the level produced by SMN2 is insufficient to protect from disease. Increasing SMN2 gene expression could be of considerable therapeutic importance. The aim of this study was to assess whether SMN2 gene expression can be increased by 4-phenylbutyrate (PBA). Fibroblast cell cultures from 16 SMA patients affected by different clinical severities were treated with PBA, and full-length SMN2 transcripts were measured by real-time PCR. In all cell cultures, except one, PBA treatment caused an increase in full-length SMN2 transcripts, ranging from 50 to 160% in type I and from 80 to 400% in type II and III cultures. PBA was found also effective in enhancing SMN protein levels and the number of SMN-containing nuclear structures (gems). These data show that SMN expression is considerably increased by PBA, and suggest that the compound, owing also to its favorable pharmacological properties, could be a good candidate for the treatment of SMA.

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Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate

Cited by 33 publications

References 0 publications

Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients

Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients

Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy

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