1. Sodium butyrate functions as an antidepressant and improves cognition with enhanced neurotrophic expression in models of maternal deprivation and chronic mild stress.
2. Sodium Butyrate, a Histone Deacetylase Inhibitor, Reverses Behavioral and Mitochondrial Alterations in Animal Models of Depression Induced by Early- or Late-life Stress.
3. Sodium butyrate and mood stabilizers block ouabain-induced hyperlocomotion and increase BDNF, NGF and GDNF levels in brain of Wistar rats.
Sodium butyrate (NaB), the sodium salt form of butyrate commonly used in pharmacological studies, is a well-known HDAC inhibitor that results in increased histone acetylation when applied to cells in culture in the high micromolar range [20], [21]. Studies from our own lab demonstrated that NaB treatment could resist oxidative stress in vitro and in vivo [22], [23], [24], [25]. These salutary effects were highly correlated with HDAC inhibition as a mechanism of protection. In multiple models of Huntington’s disease, we have shown that NaB and phenylbutyrate, a structurally similar analog, rescues histone acetylation, prevents neuronal cell death and extends the lifespan of mice [23], [26].
Numerous subsequent studies have shown that NaB’s salutary effects span many neurological disease models and aspects of the pathophysiology of disease. For example, NaB can protect neurons from cell death in models of Parkinson’s disease [27], [28], [29] and in cisplatin-induced hearing loss [30], where NaB was able to reverse the disease-associated reduction in histone acetylation. Similarly, NaB was able to reduce the infarct size in models of ischemic stroke, limiting the damage to the brain and improving behavioral outcomes [24], [31], [32], [33]. In vitro and in vivo (via intraperitoneal injection) data from our own laboratory also suggests that butyrate can induce resistance to oxidative stress and increase histone acetylation and enhance gene expression of a number of genes in the high micromolar range [24], [34]. Altogether, these observations are consistent with the idea that NaB can modulate the expression of a large number of genes to affect numerous pathophysiological pathways. The prospect of accomplishing this goal with a single, naturally occurring small molecule is exciting.
NaB has also demonstrated a profound effect on improving learning and memory, particularly in cases of disease-associated or toxicity-induced dementia. In mouse models of Alzheimer’s disease, histone acetylation is restored and expression of learning-associated genes is increased with NaB treatment [35], [36]. While NaB had no effect on the contextual memory on wild-type mice, contextual memory in the transgenic mouse model showed significant improvements, even at late stages of Alzheimer’s disease. These improvements in learning and memory have also been demonstrated in models of memory impairment from a toxic overload of metals [37], [38], traumatic brain injury [39] or neurological infections [40], [41].
As HDAC inhibitors influence the transcription of numerous genes, it seems unlikely that a single gene is responsible for its neurotrophic effects. However, many studies have shown that at least some of these beneficial effects can be attributed NaB’s ability to increase acetylation around the promoters of neurotrophic factors, such as BDNF, GDNF and NGF and thus increasing their transcription [41], [42], [43], [44], [45], [46], [47], [48]. Other studies have demonstrated the importance of immediate early genes, including c-Fos and Homer1a, which are activity dependent genes involved in plasticity [44], [49], [50], [51], [52]. Based on these data, NaB is capable of upregulating a suite of genes that promote survival, plasticity and regeneration.
2. Sodium Butyrate, a Histone Deacetylase Inhibitor, Reverses Behavioral and Mitochondrial Alterations in Animal Models of Depression Induced by Early- or Late-life Stress.
3. Sodium butyrate and mood stabilizers block ouabain-induced hyperlocomotion and increase BDNF, NGF and GDNF levels in brain of Wistar rats.
Sodium butyrate (NaB), the sodium salt form of butyrate commonly used in pharmacological studies, is a well-known HDAC inhibitor that results in increased histone acetylation when applied to cells in culture in the high micromolar range [20], [21]. Studies from our own lab demonstrated that NaB treatment could resist oxidative stress in vitro and in vivo [22], [23], [24], [25]. These salutary effects were highly correlated with HDAC inhibition as a mechanism of protection. In multiple models of Huntington’s disease, we have shown that NaB and phenylbutyrate, a structurally similar analog, rescues histone acetylation, prevents neuronal cell death and extends the lifespan of mice [23], [26].
Numerous subsequent studies have shown that NaB’s salutary effects span many neurological disease models and aspects of the pathophysiology of disease. For example, NaB can protect neurons from cell death in models of Parkinson’s disease [27], [28], [29] and in cisplatin-induced hearing loss [30], where NaB was able to reverse the disease-associated reduction in histone acetylation. Similarly, NaB was able to reduce the infarct size in models of ischemic stroke, limiting the damage to the brain and improving behavioral outcomes [24], [31], [32], [33]. In vitro and in vivo (via intraperitoneal injection) data from our own laboratory also suggests that butyrate can induce resistance to oxidative stress and increase histone acetylation and enhance gene expression of a number of genes in the high micromolar range [24], [34]. Altogether, these observations are consistent with the idea that NaB can modulate the expression of a large number of genes to affect numerous pathophysiological pathways. The prospect of accomplishing this goal with a single, naturally occurring small molecule is exciting.
NaB has also demonstrated a profound effect on improving learning and memory, particularly in cases of disease-associated or toxicity-induced dementia. In mouse models of Alzheimer’s disease, histone acetylation is restored and expression of learning-associated genes is increased with NaB treatment [35], [36]. While NaB had no effect on the contextual memory on wild-type mice, contextual memory in the transgenic mouse model showed significant improvements, even at late stages of Alzheimer’s disease. These improvements in learning and memory have also been demonstrated in models of memory impairment from a toxic overload of metals [37], [38], traumatic brain injury [39] or neurological infections [40], [41].
As HDAC inhibitors influence the transcription of numerous genes, it seems unlikely that a single gene is responsible for its neurotrophic effects. However, many studies have shown that at least some of these beneficial effects can be attributed NaB’s ability to increase acetylation around the promoters of neurotrophic factors, such as BDNF, GDNF and NGF and thus increasing their transcription [41], [42], [43], [44], [45], [46], [47], [48]. Other studies have demonstrated the importance of immediate early genes, including c-Fos and Homer1a, which are activity dependent genes involved in plasticity [44], [49], [50], [51], [52]. Based on these data, NaB is capable of upregulating a suite of genes that promote survival, plasticity and regeneration.
