Progressive and selective changes in neurotrophic factor expression and substance p axonal transport induced by perinatal diabetes: Protective action of antioxidant treatment

Abstract

Diabetes-induced embryo malformations and growth retardation are correlated with a variety of biochemical changes including oxidative stress. In this study, we show that the morphological alterations are correlated with progressive and selective changes of mRNA expression in specific neurotrophic factors. At embryological stage E-17, diabetes affected both embryo growth and NGF mRNA expression, which was reduced by as much as 90 and 56% in target tissues of sensory system such as tongue and intestine, respectively. The reduction in retina and heart was around 50%. Conversely, the mRNA expression of low-affinity neurotrophin receptor p75 was increased. At birth, BDNF mRNA expression was affected with a significant generalized reduction,while in vibrissae we observed a reduction of BDNF and p75 mRNAs and an increase of NGF. At postnatal day 14, pups from diabetic mothers showed reduced muscle levels of IGF-I, while we observed a partial impairment of substance P axonal transport at postnatal day 28. Treatment of diabetic mothers with silybin, a flavonoid with antioxidant properties, prevented most of the changes in neurotrophic factor expression and substance P axonal transport with no effects on hyperglycemia and embryo growth retardation. These results indicate that oxidative stress may influence neurotrophic factor synthesis in target territories during development. In addition, these data suggest that nervous system abnormalities observed in diabetic embryopathy may also derive by insufficient neurotrophic factor biosynthesis involving sequentially NGF in the embryo and BDNF and IGF-I in the early postnatal days. Insulin treatment of diabetic mothers normalized hyperglycemia and body growth, with consequent regular embryonic and postnatal development.

Nerve growth factor, birth outcome and pre‐eclampsia

“…Our earlier study in preeclamptic women reports increased oxidative stress (Mehendale et al, 2008) which is associated with dysregulation of angiogenic factors (Kulkarni et al, 2010) in preeclamptic women. It can be speculated that increased oxidative stress in preeclamptic women may also affect the NGF synthesis since oxidative stress has been shown to influence neurotrophic factor synthesis during development (Germani et al, 1999). Furthermore, maternal plasma NGF levels are significantly reduced while the blood pressure was significantly increased in PE‐LBW group as compared to the PE‐NBW group suggesting that NGF synthesis is also associated with the severity of pre‐eclampsia.…”

Silybin and Silymarin - New and Emerging Applications in Medicine

“…Treatment of diabetic mothers (dogs) with silybin prevented most of the changes in neurotrophic factor expression and substance P axonal transport with no effects on hyperglycemia and embryo growth retardation [113]. Treatment of diabetic mothers (dogs) with silybin prevented most of the changes in neurotrophic factor expression and substance P axonal transport with no effects on hyperglycemia and embryo growth retardation [113].…”

Early postnatal overnutrition: Potential roles of gastrointestinal vagal afferents and brain-derived neurotrophic factor

“…We focused on the BDNF gene for several reasons. First, APN and related perinatal manipulations that affect adult health (e.g., maternal deprivation) alter expression levels of key feeding hormones, neuromodulators, and receptors (or receptor sensitivity), including BDNF and its receptor, trkB, in both CNS and peripheral tissues [9, 10, 40, 42, 64–70]. Second, BDNF is present in the developing and mature GI tract.…”

“…If obesogenic diets do act similarly in both of these models, then the decrease in anorexigen levels that results from consumption of these diets would combine with the reduced threshold for hyperphagia caused by APN to push the organism past this threshold. Interestingly, APN and other perinatal manipulations that affect adult health alter the expression of hormones, neuromodulators, or receptors (or receptor sensitivity) important for regulating feeding in both CNS and peripheral tissues, including BDNF and trkB [9, 10, 40, 42, 64–70]. Some of these changes in anorexigen and orexigen signaling produced by APN may combine with changes in the same (or other) signaling pathways produced by consumption of an HE diet to push an organism across the threshold for hyperphagia.…”

“…A gene that is a strong candidate for this role is brain-derived neurotrophic factor (BDNF). Brain-derived neurotrophic factor expression is altered in both central and peripheral tissues by APN and related perinatal manipulations [9, 10]. Also, vagal afferents that innervate the GI tract are dependent on BDNF for normal development [11].…”