Post by Max on Jun 12, 2005 4:31:46 GMT -5
Vitamin A extensively linked to adult CNS function
Since retinoids readily enter the central nervous system, Vitamin A neurotoxicity in adults is possible from excessive consumption of supplements [2 and more]. In the cerebrum, cerebellum and meninges, rates of all-trans-retinoic-acid (ATRA) synthesis were comparable to, or exceeded, rates measured in rat liver [2]. In human acne-subjects, Roaccutane is taken in a 50-100 times overdose of the by consensus recommended daily intake of vitamin A, which is 0,8 micrograms*. (Ro)accutane is admininstrated to human acne-subjects during several months, which if less than one week of (Ro)accutane "therapy" results in a dose similiar to one years consumption, the cumulative dose represents the use of several decades of vitamin A consumption. In recent studies, it has been shown that all participating human subjects in studies of (Ro)accutane showed significant metabolic changes in the brain, whereas effects on the nervous system can be seen as a predictable consequence, and not only a possibililty.
Neural stem cells (NSCs) are the self-renewing, multipotent cells that generate neurons, astrocytes, and oligodendrocytes in the nervous system. Contrary to the long-held dogma, neurogenesis occurs in discrete areas of the adult brain, the hippocampus and the subventricular zone, and NSCs reside in the adult central nervous system. Recent studies have shown that neurogenesis is increased in the diseased brains, after strokes and traumatic brain injuries, and that new neuronal cells are generated at the sites of injury, where they replace some of the degenerated nerve cells [5]. It is not known to which degree the (Ro)accutane induced CNS effects are repaired through replacement by neuronal stem-cells. It is not known, whether a partial replacement by neuronal stem-cells after a suggested (Ro)accutane traumatic degenerative exposure in human acne-subjects has a diminishing effect on the remaining NSC:s, thus causing a more limited repair throughout life.
Suggested inhibitory effects on several neurotransmitters, including serotonin, acetylcholine, melatonin, norephinephrine, and other neurosteroids
Potential targets for retinoid signalling in depression include dopaminergic, serotonergic or noradrenergic pathways or a complex interaction between these neurotransmitter systems [7]. As seen in this chapter, there are even more singnaling systems in the human brain suggested to be involved in mood and well-being that with high certainity are affected in subjects exposed to (Ro)accutane (reviewed in section 2.1-2.6).
Significant metabolic changes in human acne- subjects measured that were exposed to (Ro)accutane
A mean -21% fall in metabolism the orbitofrontal cortex in human subjects exposed to (Ro)accutane was observed. Brain functioning in adults was measured with [(18)F]fluorodeoxyglucose positron emission tomography before and after 4 months of treatment with isotretinoin (N=13) or an antibiotic (N=15). Isotretinoin but not antibiotic treatment was associated with decreased brain metabolism in the orbitofrontal cortex (-21% change versus 2% change for antibiotic), a brain area known to mediate symptoms of depression [1].
Picture 1. Bremner JD et al. Functional brain imaging alterations in acne patients treated with isotretinoin. (2005) Am J Psychiatry. May;162(5):983-91.
Suggested significant cell losses in hippocampus in subjects exposed to (Ro)accutane, further losses in other areas can not be excluded
In a mouse model, it was shown that endogenous RA generated by synthetic enzymes in the meninges acts on hippocampal granule neurons, and chronic (3-week) exposure to a clinical dose of 13-cis RA may result in hippocampal cell loss [3]. Similiar effects in the subventricular zone of rats have been experimentally observed. In adult rat brains, both retinoic acid and thyroid hormone have shown to regulate differentiation and proliferation of precursor cells in the subventricular zone (SVZ) [6]. Similiar effects in humans are highly likely. Further yet not described affected areas of the mammalian brain in association with (Ro)accutane exposure in a similiar manner are highly likely. (the areas of the brain suggested to be affected are reviewed under section 2.1.1-2.1.5).
Severely Roaccutane induced disruption of retinoid signaling and suggested irreversible alteration of retinoid signaling
Retinoid signalling plays an important role in the function of the mature human brain. Components of the metabolic pathway for retinoids have been identified in adult brain tissues, suggesting that all-trans-retinoic acid (ATRA) can be synthesized in discrete regions of the human brain. The distribution of retinoid receptor proteins in the adult nervous system is different from that seen during development; and suggests that retinoid signalling is likely to have a physiological role in adult cortex, amygdala, hypothalamus, hippocampus, striatum and associated brain regions. A number of neuronal specific genes contain recognition sequences for the retinoid receptor proteins and can be directly regulated by retinoids [2]. In adult rats, CRABP-I is expression in specific populations of brain neurons suggests that RA is extensively metabolized in mature brains, mostly in neurons. Additionally, the genetic basis of its specific expression in these brain areas is located in the 5' regulatory region of this gene [4].
Disruption of retinoid signalling pathways in rodent models indicates their involvement in regulating synaptic plasticity and associated learning and memory behaviours. Retinoid signalling pathways have also been implicated in the pathophysiology of Alzheimer's disease, schizophrenia and depression. Overall, the data underscore the likely importance of adequate nutritional Vitamin A status for adult brain function and highlight retinoid signalling pathways as potential novel therapeutic targets for neurological diseases [2].
Significantly elevated 8-OHdG in human subjects exposed to (Ro)accutane - highly likely one of the relevant markers for (Ro)accutane induced oxidative DNA damage
High serum levels of 8-OHdG in acne-subjects exposed to isotretinoine may be due to a direct effect on liver, muscle and skin epidermal cells. Regular evaluation of 8-OHdG in sera of patients, especially of exposed women of reproductive age, could be a sensitive follow-up biomarker of DNA oxidation [8]. In the rat-brain, elevated 8-OHdG is a suggested marker for oxidative stress and correlated with degenerative changes [9].
Human subjects with CA (n=18) were evaluated before and 45 days after Iso (0.5mg/kg per day) exposure and non-diseased controls (n=22) were tested only once. Plasma TAS levels and 8-OHdG were measured spectrophotometrically and with an immunoassay, respectively. Liver biochemical parameters and muscle enzymes were measured on a blood chemistry analyzer. Results: TAS levels were significantly (p<0.0001) lower in patients before treatment (921+/-124 mumol/L) compared with those after treatment (1335+/-93 mumol/L) and in controls (1536+/-126 mumol/L). In contrast, 8-OHdG serum levels were two-fold higher in patients after exposure (0.21+/-0.03 ng/mL) than before exposure (0.11+/-0.02 ng/mL) and three-fold higher than in controls (0.07+/-0.01 ng/mL; p<0.0001). Negative correlations were found between TAS and 8-OHdG (r=-0.754, p<0.0001) in patients before therapy and positive correlations were found between creatine kinase (CK) and 8-OHdG (r=0.488, p<0.001) and liver enzymes after isotretinoine exposure [8].
Significantly elevated 8-hydroxy-2'-deoxyguanosine (8-OHdG) as an index of oxidative stress in the brain of rats exposed to arsenic
To clarify the association between oxidative DNA damage and the neurotoxicity of arsenic, the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as an index of oxidative DNA damage in the brain was examined in mice fed with drinking water containing 1 or 2 ppm arsenic, using an HPLC-electrochemical detector and immunohistochemical method. 8-OHdG levels were significantly increased in the brain of mice given arsenic and its immunoreactivity was distributed in the cerebral and cerebellar cortexes. Cerebral cortex neurons and Purkinje cells in the cerebellar cortex showed degenerative changes in accordance with the distribution of 8-OHdG immunoreactivity. The levels of arsenic in this study were lower than those reported in epidemiological studies. Thus, it is concluded that environmentally relevant levels of arsenic induce pathological changes through oxidative DNA damage in the brain tissues in vivo and that cerebral and cerebellar cortex neurons seem to be the major targets of arsenic neurotoxicity [9].
Most cells that are active in neurotransmission express action through g-protein-coupled receptors. Interaction bewtween retinoic acid and several types of g-proteins have been found, as well as inhibitory actions on enzymes that metabolize neurotranmittors. TGF-beta is found to be upregulated in subjects exposed to retinoic acid.
CYP2C6
CYP2D6
tryptofan hydroxylase - alkaline phosphatase
tyrosine hydroxylase
g-protein coupled receptors
TGF-beta
*Consensus by the Food and Nutritional labeling dep. of the european union
Since retinoids readily enter the central nervous system, Vitamin A neurotoxicity in adults is possible from excessive consumption of supplements [2 and more]. In the cerebrum, cerebellum and meninges, rates of all-trans-retinoic-acid (ATRA) synthesis were comparable to, or exceeded, rates measured in rat liver [2]. In human acne-subjects, Roaccutane is taken in a 50-100 times overdose of the by consensus recommended daily intake of vitamin A, which is 0,8 micrograms*. (Ro)accutane is admininstrated to human acne-subjects during several months, which if less than one week of (Ro)accutane "therapy" results in a dose similiar to one years consumption, the cumulative dose represents the use of several decades of vitamin A consumption. In recent studies, it has been shown that all participating human subjects in studies of (Ro)accutane showed significant metabolic changes in the brain, whereas effects on the nervous system can be seen as a predictable consequence, and not only a possibililty.
Neural stem cells (NSCs) are the self-renewing, multipotent cells that generate neurons, astrocytes, and oligodendrocytes in the nervous system. Contrary to the long-held dogma, neurogenesis occurs in discrete areas of the adult brain, the hippocampus and the subventricular zone, and NSCs reside in the adult central nervous system. Recent studies have shown that neurogenesis is increased in the diseased brains, after strokes and traumatic brain injuries, and that new neuronal cells are generated at the sites of injury, where they replace some of the degenerated nerve cells [5]. It is not known to which degree the (Ro)accutane induced CNS effects are repaired through replacement by neuronal stem-cells. It is not known, whether a partial replacement by neuronal stem-cells after a suggested (Ro)accutane traumatic degenerative exposure in human acne-subjects has a diminishing effect on the remaining NSC:s, thus causing a more limited repair throughout life.
Suggested inhibitory effects on several neurotransmitters, including serotonin, acetylcholine, melatonin, norephinephrine, and other neurosteroids
Potential targets for retinoid signalling in depression include dopaminergic, serotonergic or noradrenergic pathways or a complex interaction between these neurotransmitter systems [7]. As seen in this chapter, there are even more singnaling systems in the human brain suggested to be involved in mood and well-being that with high certainity are affected in subjects exposed to (Ro)accutane (reviewed in section 2.1-2.6).
Significant metabolic changes in human acne- subjects measured that were exposed to (Ro)accutane
A mean -21% fall in metabolism the orbitofrontal cortex in human subjects exposed to (Ro)accutane was observed. Brain functioning in adults was measured with [(18)F]fluorodeoxyglucose positron emission tomography before and after 4 months of treatment with isotretinoin (N=13) or an antibiotic (N=15). Isotretinoin but not antibiotic treatment was associated with decreased brain metabolism in the orbitofrontal cortex (-21% change versus 2% change for antibiotic), a brain area known to mediate symptoms of depression [1].
Picture 1. Bremner JD et al. Functional brain imaging alterations in acne patients treated with isotretinoin. (2005) Am J Psychiatry. May;162(5):983-91.
Suggested significant cell losses in hippocampus in subjects exposed to (Ro)accutane, further losses in other areas can not be excluded
In a mouse model, it was shown that endogenous RA generated by synthetic enzymes in the meninges acts on hippocampal granule neurons, and chronic (3-week) exposure to a clinical dose of 13-cis RA may result in hippocampal cell loss [3]. Similiar effects in the subventricular zone of rats have been experimentally observed. In adult rat brains, both retinoic acid and thyroid hormone have shown to regulate differentiation and proliferation of precursor cells in the subventricular zone (SVZ) [6]. Similiar effects in humans are highly likely. Further yet not described affected areas of the mammalian brain in association with (Ro)accutane exposure in a similiar manner are highly likely. (the areas of the brain suggested to be affected are reviewed under section 2.1.1-2.1.5).
Severely Roaccutane induced disruption of retinoid signaling and suggested irreversible alteration of retinoid signaling
Retinoid signalling plays an important role in the function of the mature human brain. Components of the metabolic pathway for retinoids have been identified in adult brain tissues, suggesting that all-trans-retinoic acid (ATRA) can be synthesized in discrete regions of the human brain. The distribution of retinoid receptor proteins in the adult nervous system is different from that seen during development; and suggests that retinoid signalling is likely to have a physiological role in adult cortex, amygdala, hypothalamus, hippocampus, striatum and associated brain regions. A number of neuronal specific genes contain recognition sequences for the retinoid receptor proteins and can be directly regulated by retinoids [2]. In adult rats, CRABP-I is expression in specific populations of brain neurons suggests that RA is extensively metabolized in mature brains, mostly in neurons. Additionally, the genetic basis of its specific expression in these brain areas is located in the 5' regulatory region of this gene [4].
Disruption of retinoid signalling pathways in rodent models indicates their involvement in regulating synaptic plasticity and associated learning and memory behaviours. Retinoid signalling pathways have also been implicated in the pathophysiology of Alzheimer's disease, schizophrenia and depression. Overall, the data underscore the likely importance of adequate nutritional Vitamin A status for adult brain function and highlight retinoid signalling pathways as potential novel therapeutic targets for neurological diseases [2].
Significantly elevated 8-OHdG in human subjects exposed to (Ro)accutane - highly likely one of the relevant markers for (Ro)accutane induced oxidative DNA damage
High serum levels of 8-OHdG in acne-subjects exposed to isotretinoine may be due to a direct effect on liver, muscle and skin epidermal cells. Regular evaluation of 8-OHdG in sera of patients, especially of exposed women of reproductive age, could be a sensitive follow-up biomarker of DNA oxidation [8]. In the rat-brain, elevated 8-OHdG is a suggested marker for oxidative stress and correlated with degenerative changes [9].
Human subjects with CA (n=18) were evaluated before and 45 days after Iso (0.5mg/kg per day) exposure and non-diseased controls (n=22) were tested only once. Plasma TAS levels and 8-OHdG were measured spectrophotometrically and with an immunoassay, respectively. Liver biochemical parameters and muscle enzymes were measured on a blood chemistry analyzer. Results: TAS levels were significantly (p<0.0001) lower in patients before treatment (921+/-124 mumol/L) compared with those after treatment (1335+/-93 mumol/L) and in controls (1536+/-126 mumol/L). In contrast, 8-OHdG serum levels were two-fold higher in patients after exposure (0.21+/-0.03 ng/mL) than before exposure (0.11+/-0.02 ng/mL) and three-fold higher than in controls (0.07+/-0.01 ng/mL; p<0.0001). Negative correlations were found between TAS and 8-OHdG (r=-0.754, p<0.0001) in patients before therapy and positive correlations were found between creatine kinase (CK) and 8-OHdG (r=0.488, p<0.001) and liver enzymes after isotretinoine exposure [8].
Significantly elevated 8-hydroxy-2'-deoxyguanosine (8-OHdG) as an index of oxidative stress in the brain of rats exposed to arsenic
To clarify the association between oxidative DNA damage and the neurotoxicity of arsenic, the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as an index of oxidative DNA damage in the brain was examined in mice fed with drinking water containing 1 or 2 ppm arsenic, using an HPLC-electrochemical detector and immunohistochemical method. 8-OHdG levels were significantly increased in the brain of mice given arsenic and its immunoreactivity was distributed in the cerebral and cerebellar cortexes. Cerebral cortex neurons and Purkinje cells in the cerebellar cortex showed degenerative changes in accordance with the distribution of 8-OHdG immunoreactivity. The levels of arsenic in this study were lower than those reported in epidemiological studies. Thus, it is concluded that environmentally relevant levels of arsenic induce pathological changes through oxidative DNA damage in the brain tissues in vivo and that cerebral and cerebellar cortex neurons seem to be the major targets of arsenic neurotoxicity [9].
Most cells that are active in neurotransmission express action through g-protein-coupled receptors. Interaction bewtween retinoic acid and several types of g-proteins have been found, as well as inhibitory actions on enzymes that metabolize neurotranmittors. TGF-beta is found to be upregulated in subjects exposed to retinoic acid.
CYP2C6
CYP2D6
tryptofan hydroxylase - alkaline phosphatase
tyrosine hydroxylase
g-protein coupled receptors
TGF-beta
*Consensus by the Food and Nutritional labeling dep. of the european union