Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase

Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung-/- embryonic fibroblasts, and conferred death of cultured Ung-/- hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung-/- but not Ung+/+ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in Ung-/- mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency

Abstract Number ‐ 81: Safety and Efficacy of Trans‐carotid Intervention in Multiple Scenarios: Medellin Experience Direct Carotid access.

Introduction Direct carotid puncture has been validated such as an alternative route to reach the intracranial vasculature. However, this approach has not been considered routinely in INR. A believe of higher risk for neurovascular procedures or major accesssite related complications restrict its use. This study was conducted to investigate the feasibility and safety of trans carotid Neurointervention for a variety of pathologies. Methods Since 2018 we implemented a direct carotid access under special considerations to perform a therapeutic approach. A total of 14 patients from our centers were analyzed. Patients were divided into a variety of neurovascular conditions: Carotid Stenting CAS (n = 2), Mechanical Thrombectomy MT (n = 5), AVM´s treatment (n = 2), intracranial Aneurysms treatment (n = 5). Patient demographics, technical data, intervention time, type of intervention, closure device used, local or systemic complications and a patient perception assessment were registered. Results Mean age was 64.3 ± 10.3 years. all cases but two we treated the patients under General Anesthesia GA. Major indication to this approach was : anatomical and access limitations. (in 12 cases wasn’t possible to reach the ICA through femoral or radial access due to extreme aortic arc tortuosity. Two patients with Leriche Syndrome) All cases performed with ultrasound US assistance. A 4 Fr. Micro‐ puncture set were used in all procedures and posteriorly a 6Fr. Introducer was inserted. Technical success in all cases (100%). Two patients presented mild vasospasm and resolved using IA vasodilators. Both CAS were performed without any complications and none embolic protection device used. For MT(n = 5): a SOFIA 6Fr for ADAPT was used in 3 cases with TICI 2b‐3 in all cases. Combined approach ¨Solumbra¨ solitaire and aspiration catheter was used in two cases, one TICI 2a and one TICI 3. For the AVM´s treatment we use a 6Fr guiding catheter and non‐detachable microcatheters to inject Onix with a high grade of obliteration. Five aneurysms were treated with this approach (2 ICA – ophthalmic; 2 MCA and one AcomA) Mean average time of the procedure was 34.5 min. (ranged 9–59 min) just one bleeding complication observed at the closure device use. In all cases but one we use Angio‐Seal 6Fr as closure device, in a single case where we used a ProGlide suture device we had a serious complication at the puncture site. Conclusions Trans Carotid Intervention TCI. was feasible and safe in selected patients in this small series. A multiple variety of neurovascular conditions would be treated successfully by this way improving the learning curve. Complication rates and clinical outcomes were comparable with those in trans femoral or radial approach

Rubratoxin B Elicits Antioxidative and DNA Repair Responses in Mouse Brain

Rubratoxin B (RB) is a mycotoxin with potential neurotoxic effects that have not yet been characterized. Based on existing evidence that RB interferes with mitochondrial electron transport to produce oxidative stress in peripheral tissues, we hypothesized that RB would produce oxidative damage to macromolecules in specific brain regions. Parameters of oxidative DNA damage and repair, lipid peroxidation, and superoxide dismutase (SOD) activity were measured across six mouse brain regions 24 h after administration of a single dose of RB. Lipid peroxidation and oxidative DNA damage were either unchanged or decreased in all brain regions in RB-treated mice compared with vehicle-treated mice. Concomitant with these decreased indices of oxidative macromolecular damage, SOD activity was significantly increased in all brain regions. Oxyguanosine glycosylase activity (OGG1), a key enzyme in the repair of oxidized DNA, was significantly increased in three brain regions—cerebellum (CB), caudate/putamen (CP), and cortex (CX)—but not in the hippocampus (HP), midbrain (MB), and pons/medulla (PM). The RB-enhanced OGG1 catalytic activity in these brain regions was not due to increased OGG1 protein expression, but was a result of enhanced catalytic activity of the enzyme. In conclusion, specific brain regions responded to an acute dose of RB by significantly altering SOD and OGG1 activities to maintain the degree of oxidative DNA damage equal to, or less than, that of normal steady-state levels

Rubratoxin B Elicits Antioxidative and DNA Repair Responses in Mouse Brain

Rubratoxin B (RB) is a mycotoxin with potential neurotoxic effects that have not yet been characterized. Based on existing evidence that RB interferes with mitochondrial electron transport to produce oxidative stress in peripheral tissues, we hypothesized that RB would produce oxidative damage to macromolecules in specific brain regions. Parameters of oxidative DNA damage and repair, lipid peroxidation, and superoxide dismutase (SOD) activity were measured across six mouse brain regions 24 h after administration of a single dose of RB. Lipid peroxidation and oxidative DNA damage were either unchanged or decreased in all brain regions in RB-treated mice compared with vehicle-treated mice. Concomitant with these decreased indices of oxidative macromolecular damage, SOD activity was significantly increased in all brain regions. Oxyguanosine glycosylase activity (OGG1), a key enzyme in the repair of oxidized DNA, was significantly increased in three brain regions—cerebellum (CB), caudate/putamen (CP), and cortex (CX)—but not in the hippocampus (HP), midbrain (MB), and pons/medulla (PM). The RB-enhanced OGG1 catalytic activity in these brain regions was not due to increased OGG1 protein expression, but was a result of enhanced catalytic activity of the enzyme. In conclusion, specific brain regions responded to an acute dose of RB by significantly altering SOD and OGG1 activities to maintain the degree of oxidative DNA damage equal to, or less than, that of normal steady-state levels