Ely neurologic ?the so-called “cerebral organic acidurias” [5]. After a pre-symptomatic period

Ely neurologic ?the so-called “cerebral organic acidurias” [5]. After a pre-symptomatic period in which macrocephaly and/or subtle Dimethylenastron neurological signs can be noticed, most children with GA-I present with an acute encephalopathic crisis that usually occurs between the 6th and 18th month of life following an intercurrent infection or immunization. During this crisis, previously acquired motor skills are lost and permanent motor handicap remains. Neuroimaging shows bilateral destruction of caudate and putamen. 1676428 A minority of patients experiences the insidious onset of this disease with delayed motor development and progressive dystonic cerebral palsy [1,6,7]. Early diagnosis and treatment allows preventing brain damage at least in part. Low lysine diet in combination with carnitine and anti-catabolicemergency treatment is the standard management in presymptomatic infants. However, up to one third of pre-symptomatically diagnosed patients (e.g. via newborn screening) encounter striatal injury or show fine motor and speech deficits [8,9,10,11]. Nearly three decades of scientific research on the origin of neurological damage in organic acidurias have only partially uncovered the mechanisms of neurotoxicity in these disorders. The “toxic metabolite” and “trapping” hypotheses suggest that the production and accumulation of putative toxic metabolites in brain are involved in the pathomechanisms of organic acidurias. Following the “toxic metabolite” theory, GA and Nobiletin 3-OHGA are supposed to be putative brain cell toxins when produced and/or accumulated in the central nervous system of GA-I patients. These theories have directed the research towards neurotoxicity studies of the main metabolites accumulating in these diseases (reviewed in [9]). Three mechanisms have been suggested to be involved in the pathogenesis of this disease: i) excitotoxicity, ii) impairment of cerebral energy metabolism and iii) induction of oxidative stress [9]. A Gcdh2/2 mouse model was generated that showed a biochemical phenotype similar to GA-I patients. Pathologically, these mice have a diffuse spongiform myelinopathy similar to that in human patients [12]. However, they do not present typical encephalopathic crises unless under high protein or high lysineBrain Cell Damage in Glutaric Aciduria Type Idiet. High protein diet is rapidly lethal, while 4 week-old Gcdh2/2 mice under high lysine develop vasogenic edema, blood-brain barrier breakdown, neuronal loss, hemorrhage, paralysis and seizures, and die after 3?2 days. In contrast, most 8-week-old Gcdh2/2 mice survive on high lysine diet, but develop white matter lesions, reactive astrocytes and neuronal loss [13]. Despite existing evidence for the role of GA and 3-OHGA in the neurotoxicity of GA-I, the neuropathogenesis of this disease still remains poorly understood. We developed an in vitro model for the study of neurotoxicity in GA-I by exposing 3D organotypic rat brain cell cultures in aggregates to GA and 3-OHGA. This model mimics the production and accumulation of these metabolites during a metabolic crisis. We analyzed the effect of GA and 3-OHGA on brain cells in immature and more developed stages of the cultures. Cell morphology, cell death, and the metabolic profile in the culture medium have been studied.Materials and Methods Ethics StatementThis study was carried out in strict accordance to the Ethical Principles and Guidelines for Scientific Experiments on Animals of the Swiss Academy for Medical Science.Ely neurologic ?the so-called “cerebral organic acidurias” [5]. After a pre-symptomatic period in which macrocephaly and/or subtle neurological signs can be noticed, most children with GA-I present with an acute encephalopathic crisis that usually occurs between the 6th and 18th month of life following an intercurrent infection or immunization. During this crisis, previously acquired motor skills are lost and permanent motor handicap remains. Neuroimaging shows bilateral destruction of caudate and putamen. 1676428 A minority of patients experiences the insidious onset of this disease with delayed motor development and progressive dystonic cerebral palsy [1,6,7]. Early diagnosis and treatment allows preventing brain damage at least in part. Low lysine diet in combination with carnitine and anti-catabolicemergency treatment is the standard management in presymptomatic infants. However, up to one third of pre-symptomatically diagnosed patients (e.g. via newborn screening) encounter striatal injury or show fine motor and speech deficits [8,9,10,11]. Nearly three decades of scientific research on the origin of neurological damage in organic acidurias have only partially uncovered the mechanisms of neurotoxicity in these disorders. The “toxic metabolite” and “trapping” hypotheses suggest that the production and accumulation of putative toxic metabolites in brain are involved in the pathomechanisms of organic acidurias. Following the “toxic metabolite” theory, GA and 3-OHGA are supposed to be putative brain cell toxins when produced and/or accumulated in the central nervous system of GA-I patients. These theories have directed the research towards neurotoxicity studies of the main metabolites accumulating in these diseases (reviewed in [9]). Three mechanisms have been suggested to be involved in the pathogenesis of this disease: i) excitotoxicity, ii) impairment of cerebral energy metabolism and iii) induction of oxidative stress [9]. A Gcdh2/2 mouse model was generated that showed a biochemical phenotype similar to GA-I patients. Pathologically, these mice have a diffuse spongiform myelinopathy similar to that in human patients [12]. However, they do not present typical encephalopathic crises unless under high protein or high lysineBrain Cell Damage in Glutaric Aciduria Type Idiet. High protein diet is rapidly lethal, while 4 week-old Gcdh2/2 mice under high lysine develop vasogenic edema, blood-brain barrier breakdown, neuronal loss, hemorrhage, paralysis and seizures, and die after 3?2 days. In contrast, most 8-week-old Gcdh2/2 mice survive on high lysine diet, but develop white matter lesions, reactive astrocytes and neuronal loss [13]. Despite existing evidence for the role of GA and 3-OHGA in the neurotoxicity of GA-I, the neuropathogenesis of this disease still remains poorly understood. We developed an in vitro model for the study of neurotoxicity in GA-I by exposing 3D organotypic rat brain cell cultures in aggregates to GA and 3-OHGA. This model mimics the production and accumulation of these metabolites during a metabolic crisis. We analyzed the effect of GA and 3-OHGA on brain cells in immature and more developed stages of the cultures. Cell morphology, cell death, and the metabolic profile in the culture medium have been studied.Materials and Methods Ethics StatementThis study was carried out in strict accordance to the Ethical Principles and Guidelines for Scientific Experiments on Animals of the Swiss Academy for Medical Science.

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