Results: All tested hydroxamates showed no or greatly reduced teratogenic potency in mice compared to the free acids. Furthermore all compounds exhibited anticonvulsant activity with ED50 doses ranging from 0.16 mmol/kg to 0.59
mmol/kg (VPA 0.57 mmol/kg). Neurotoxicity of the hydroxamates was increased compared to VPA. TD50 doses range from 0.70 mmol/kg to 1.42 mmol/kg (VPA 1.83 mmol/kg).
Conclusion: Hydroxamic acid derivatives of VPA with improved protective index and little or undetectable teratogenic potency compared to the free acids are described. alpha-fluorination of VPA also resulted in loss of teratogenic activity. Such fluorination of the hydroxamic acids also led to compounds with an improved anticonvulscant profile compared to non-fluorinated hydroxamates. The non-chiral 2-Fluror-VPA-hydroxamic
Evofosfamide datasheet find more acid was the most promising compound with a protective index (ratio of TD50 to ED50) of 4.4 compared to 3.2 for VPA. This compound combines an improved ratio of anticonvulsant potency/neurotoxicity with the advantage of not being teratogenic in the mouse neural tube defect model used. (C) 2008 Published by Elsevier Inc.”
“Tubuloglomerular feedback (TGF) describes a causal and direct relationship between tubular NaCl concentration at the end of the ascending limb of the loop of Henle and afferent arteriolar tone. The use of genetically altered mice has led to an expansion of our understanding of the mechanisms underlying the functional coupling of epithelial, mesangial, and vascular cells in TGF. Studies in mice with deletions of the A or B isoform of NKCC2 (Na,K,2Cl cotransporter) and of ROMK indicate that NaCl uptake is required for response initiation. A role for transcellular salt transport is suggested by the inhibitory effect of ouabain in mutant mice with an ouabain-sensitive alpha 1 Na,K-ATPase. No effect on TGF was observed in NHE2- and H/K-ATPase-deficient mice. TGF responses are abolished in A1 adenosine
receptor-deficient mice, and studies in mice with null mutations in NTPDase1 or ecto-5′-nucleotidase indicate that adenosine involved in TGF is mainly derived from dephosphorylation of released ATP. Angiotensin II is a required cofactor for the elicitation of TGF responses, as AT1 receptor or angiotensin-converting enzyme deficiencies reduce TGF responses, mostly SB-3CT by reducing adenosine effectiveness. Overall, the evidence from these studies in genetically altered mice indicates that transcellular NaCl transport induces the generation of adenosine that, in conjunction with angiotensin II, elicits afferent arteriolar constriction.”
“Neurofunctional effects produced by gestational all-trans retinoic acid (all-trans RA) treatment were investigated in the offspring of Sprague-Dawley rats. Reproduction data, onset of reflexive behavior, locomotor activity, motor coordination and motor learning were examined. Moreover, possible changes in size and morphology of the cerebellum were evaluated.