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Fetal Alcohol Spectrum Disorder (FASD) Associated Neural Defects: Complex Mechanisms and Potential Therapeutic Targets.

Muralidharan P, Sarmah S, Zhou FC, Marrs JA - Brain Sci (2013)

Bottom Line: Proposed mechanisms include cell death, cell signaling defects and gene expression changes.More recently, the involvement of several other molecular pathways was explored, including non-coding RNA, epigenetic changes and specific vitamin deficiencies.These various pathways may interact, producing a wide spectrum of consequences.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA. pmuralid@iupui.edu.

ABSTRACT
Fetal alcohol spectrum disorder (FASD), caused by prenatal alcohol exposure, can result in craniofacial dysmorphism, cognitive impairment, sensory and motor disabilities among other defects. FASD incidences are as high as 2% to 5 % children born in the US, and prevalence is higher in low socioeconomic populations. Despite various mechanisms being proposed to explain the etiology of FASD, the molecular targets of ethanol toxicity during development are unknown. Proposed mechanisms include cell death, cell signaling defects and gene expression changes. More recently, the involvement of several other molecular pathways was explored, including non-coding RNA, epigenetic changes and specific vitamin deficiencies. These various pathways may interact, producing a wide spectrum of consequences. Detailed understanding of these various pathways and their interactions will facilitate the therapeutic target identification, leading to new clinical intervention, which may reduce the incidence and severity of these highly prevalent preventable birth defects. This review discusses manifestations of alcohol exposure on the developing central nervous system, including the neural crest cells and sensory neural placodes, focusing on molecular neurodevelopmental pathways as possible therapeutic targets for prevention or protection.

No MeSH data available.


Related in: MedlinePlus

Proposed mechanism for ethanol-induced oxidative stress-mediated cell death. Ethanol can act as an oxidant by inducing the production of reactive oxidative species (ROS) during ethanol degradation. ROS can induce translocation of pro-apoptotic proteins, BAX/BAK to the mitochondrial membrane leading to disruption of membrane integrity. The resulting cytochrome c release induces caspase cascade, leading to apoptosis. Cytochrome c release also causes increased superoxide formation and enhanced ROS production. This leads to protein oxidation, lipid peroxidation and DNA damage, which can enhance apoptosis induction pathways. Vitamin E and neurotrophic factors such as BDNF and NT3 are known to inhibit BAX/BAK translocation and apoptosis. Anti-apoptotic proteins such as Bcl-2 and Bcl-xl are also affected by to reduced vitamin E (VE) and BDNF. Ethanol reduces vitamin E and neurotrophic factors, which in turn affect Bcl-2 and Bcl-xl. Together, ethanol promotes BAX/BAK translocation to mitochondrial membrane, leading to apoptosis. Key genes like Nrf-2 regulate antioxidant enzymes, including superoxide dismutase and catalase. This is reduced in ethanol-treated cells. Black lines/arrows indicate normal pathway for cell death, and red lines/arrows indicate ethanol-induced changes, increase or decrease. Green boxes indicate therapeutic targets that have been tested for rescue of oxidative-stress mediated cell death.
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brainsci-03-00964-f004: Proposed mechanism for ethanol-induced oxidative stress-mediated cell death. Ethanol can act as an oxidant by inducing the production of reactive oxidative species (ROS) during ethanol degradation. ROS can induce translocation of pro-apoptotic proteins, BAX/BAK to the mitochondrial membrane leading to disruption of membrane integrity. The resulting cytochrome c release induces caspase cascade, leading to apoptosis. Cytochrome c release also causes increased superoxide formation and enhanced ROS production. This leads to protein oxidation, lipid peroxidation and DNA damage, which can enhance apoptosis induction pathways. Vitamin E and neurotrophic factors such as BDNF and NT3 are known to inhibit BAX/BAK translocation and apoptosis. Anti-apoptotic proteins such as Bcl-2 and Bcl-xl are also affected by to reduced vitamin E (VE) and BDNF. Ethanol reduces vitamin E and neurotrophic factors, which in turn affect Bcl-2 and Bcl-xl. Together, ethanol promotes BAX/BAK translocation to mitochondrial membrane, leading to apoptosis. Key genes like Nrf-2 regulate antioxidant enzymes, including superoxide dismutase and catalase. This is reduced in ethanol-treated cells. Black lines/arrows indicate normal pathway for cell death, and red lines/arrows indicate ethanol-induced changes, increase or decrease. Green boxes indicate therapeutic targets that have been tested for rescue of oxidative-stress mediated cell death.

Mentions: Vitamin E (VE), α-tocopherol, is a powerful antioxidant and is known to offer protection from ethanol induced neurotoxicity [75,76,77]. During pregnancy, VE deficiency causes several developmental abnormalities and behavioral deficits, which may cause oxidative stress of the rapidly growing embryo [78]. Among the many mechanisms thought to contribute to the etiology of FASD, ethanol induced apoptosis caused by reactive oxygen species (ROS) is well supported and studied. Natural VE can protect against ethanol-induced neurotoxicity in a rat hippocampal cell culture FAS model by preventing lipid peroxidation and preserving membrane integrity, perhaps by scavenging damaging free radicals. Experiments by Heaton et al. [79] showed that VE supplementation significantly stimulated secretion of neurotrophic factors such as BDNF, NT-3 and upregulation of anti-apoptotic molecules including Bcl-2, Bcl-xl and pAkt (Figure 4). These effects could promote cell survival and reduce toxic ROS [79].


Fetal Alcohol Spectrum Disorder (FASD) Associated Neural Defects: Complex Mechanisms and Potential Therapeutic Targets.

Muralidharan P, Sarmah S, Zhou FC, Marrs JA - Brain Sci (2013)

Proposed mechanism for ethanol-induced oxidative stress-mediated cell death. Ethanol can act as an oxidant by inducing the production of reactive oxidative species (ROS) during ethanol degradation. ROS can induce translocation of pro-apoptotic proteins, BAX/BAK to the mitochondrial membrane leading to disruption of membrane integrity. The resulting cytochrome c release induces caspase cascade, leading to apoptosis. Cytochrome c release also causes increased superoxide formation and enhanced ROS production. This leads to protein oxidation, lipid peroxidation and DNA damage, which can enhance apoptosis induction pathways. Vitamin E and neurotrophic factors such as BDNF and NT3 are known to inhibit BAX/BAK translocation and apoptosis. Anti-apoptotic proteins such as Bcl-2 and Bcl-xl are also affected by to reduced vitamin E (VE) and BDNF. Ethanol reduces vitamin E and neurotrophic factors, which in turn affect Bcl-2 and Bcl-xl. Together, ethanol promotes BAX/BAK translocation to mitochondrial membrane, leading to apoptosis. Key genes like Nrf-2 regulate antioxidant enzymes, including superoxide dismutase and catalase. This is reduced in ethanol-treated cells. Black lines/arrows indicate normal pathway for cell death, and red lines/arrows indicate ethanol-induced changes, increase or decrease. Green boxes indicate therapeutic targets that have been tested for rescue of oxidative-stress mediated cell death.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061856&req=5

brainsci-03-00964-f004: Proposed mechanism for ethanol-induced oxidative stress-mediated cell death. Ethanol can act as an oxidant by inducing the production of reactive oxidative species (ROS) during ethanol degradation. ROS can induce translocation of pro-apoptotic proteins, BAX/BAK to the mitochondrial membrane leading to disruption of membrane integrity. The resulting cytochrome c release induces caspase cascade, leading to apoptosis. Cytochrome c release also causes increased superoxide formation and enhanced ROS production. This leads to protein oxidation, lipid peroxidation and DNA damage, which can enhance apoptosis induction pathways. Vitamin E and neurotrophic factors such as BDNF and NT3 are known to inhibit BAX/BAK translocation and apoptosis. Anti-apoptotic proteins such as Bcl-2 and Bcl-xl are also affected by to reduced vitamin E (VE) and BDNF. Ethanol reduces vitamin E and neurotrophic factors, which in turn affect Bcl-2 and Bcl-xl. Together, ethanol promotes BAX/BAK translocation to mitochondrial membrane, leading to apoptosis. Key genes like Nrf-2 regulate antioxidant enzymes, including superoxide dismutase and catalase. This is reduced in ethanol-treated cells. Black lines/arrows indicate normal pathway for cell death, and red lines/arrows indicate ethanol-induced changes, increase or decrease. Green boxes indicate therapeutic targets that have been tested for rescue of oxidative-stress mediated cell death.
Mentions: Vitamin E (VE), α-tocopherol, is a powerful antioxidant and is known to offer protection from ethanol induced neurotoxicity [75,76,77]. During pregnancy, VE deficiency causes several developmental abnormalities and behavioral deficits, which may cause oxidative stress of the rapidly growing embryo [78]. Among the many mechanisms thought to contribute to the etiology of FASD, ethanol induced apoptosis caused by reactive oxygen species (ROS) is well supported and studied. Natural VE can protect against ethanol-induced neurotoxicity in a rat hippocampal cell culture FAS model by preventing lipid peroxidation and preserving membrane integrity, perhaps by scavenging damaging free radicals. Experiments by Heaton et al. [79] showed that VE supplementation significantly stimulated secretion of neurotrophic factors such as BDNF, NT-3 and upregulation of anti-apoptotic molecules including Bcl-2, Bcl-xl and pAkt (Figure 4). These effects could promote cell survival and reduce toxic ROS [79].

Bottom Line: Proposed mechanisms include cell death, cell signaling defects and gene expression changes.More recently, the involvement of several other molecular pathways was explored, including non-coding RNA, epigenetic changes and specific vitamin deficiencies.These various pathways may interact, producing a wide spectrum of consequences.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA. pmuralid@iupui.edu.

ABSTRACT
Fetal alcohol spectrum disorder (FASD), caused by prenatal alcohol exposure, can result in craniofacial dysmorphism, cognitive impairment, sensory and motor disabilities among other defects. FASD incidences are as high as 2% to 5 % children born in the US, and prevalence is higher in low socioeconomic populations. Despite various mechanisms being proposed to explain the etiology of FASD, the molecular targets of ethanol toxicity during development are unknown. Proposed mechanisms include cell death, cell signaling defects and gene expression changes. More recently, the involvement of several other molecular pathways was explored, including non-coding RNA, epigenetic changes and specific vitamin deficiencies. These various pathways may interact, producing a wide spectrum of consequences. Detailed understanding of these various pathways and their interactions will facilitate the therapeutic target identification, leading to new clinical intervention, which may reduce the incidence and severity of these highly prevalent preventable birth defects. This review discusses manifestations of alcohol exposure on the developing central nervous system, including the neural crest cells and sensory neural placodes, focusing on molecular neurodevelopmental pathways as possible therapeutic targets for prevention or protection.

No MeSH data available.


Related in: MedlinePlus