Cristina Finco

Effects of low doses of glycosaminoglycans and insulin-like growth factor-I on motor neuron disease in wobbler mouse

In this study we examined the effects of insulin-like growth factor-I (IGF-I) and of glycosaminoglycans (GAGs) on the progressive motor neuron disease in wobbler mice. After clinical diagnosis at age 3 weeks, mice received daily subcutaneous injections of IGF-I, or GAGs, or saline for 3 weeks. The histometric analysis revealed that biceps muscle fiber diameter was reduced in wobbler mice and that treatments with GAGs and IGF-I prevented such a drop. The number of atrophic small fibers was markedly reduced and that of the larger ones augmented. No effects on body growth and biceps muscle weight were observed. The combined AChE-silver staining revealed that both treatments promoted intramuscular axonal sprouting. The typical decline of grip strength in wobbler mice was also prevented. This study suggests that GAGs and IGF-I administrations can retard the onset of motor deficit, and reduce muscle atrophy in wobbler mice.

Perinatal morphine exposure alters peptidergic development in the striatum

It has been reported that perinatal exposure to opiates affects mRNA synthesis, body growth and brain development in mammals, including humans. We have observed that morphine administration in drinking water during the perinatal period alters peptide development in the striatum of the rat. There is a marked increase in substance P and met‐enkephalin content, the latter is maintained even at 30 days postnatally. The transient increase or earlier maturation of substance P content is correlated by a more precocious axon terminal organization as revealed by immunocytochemical staining. The increased metenkephalin content is correlated by a higher abundance of preproenkephalin A mRNA and this correlation is particularly evident at 15 days postnatally. At earlier times both northern blotting and in situ hybridization techniques fail to show any significant difference between control and morphine exposed rats, likely because the peptide content is not very different in the two groups or at least the gap is not as wide as at later times.

Alterations of protein mono-ADP-ribosylation and diabetic neuropathy: a novel pharmacological approach

This study monitored the extranuclear endogenous mono ADP-ribosylation of proteins. At least 10 proteins were ADP-ribosylated in a crude extract from control superior cervical ganglia, and 7 were labeled in control dorsal root ganglia; whereas in the diabetic rat the extent of labeling was reduced. These data suggest that proteins of peripheral ganglia are excessively ADP-ribosylated in vivo. Treatment of diabetic animals with silybin, a flavonoid with ADP-ribosyltransferase inhibitory activity, did not affect hyperglycemia, but prevented the alterations in the extent of mono-ADP-ribosylation of proteins. This effect was associated with the prevention of substance P-like immunoreactivity loss in the sciatic nerve. In the membrane fraction of sciatic nerve Schwann cells, at least 9 proteins were ADP-ribosylated, in diabetic rats the extent of labeling was increased. A comparable increase involving the same proteins was triggered by chronic nerve injury and by corticosteroid treatment. Silybin treatment of diabetic rats prevented such an increase. We propose that the inhibition of excessive protein mono-ADP-ribosylation by silybin prevented the onset of diabetic neuropathy, while the silybin effect on mono-ADP-ribosylation of Schwann cells is likely indirect and secondary to the improvement of diabetic axonopathy.

Endogenous Mono-ADP-Ribosylation in Retina and Peripheral Nervous System

The extranuclear endogenous mono-ADP-ribosylation of proteins was monitored in cellular preparations of retina, superior cervical ganglion, dorsal root ganglia and peripheral nerve. At least 6 protein fractions are ADP-ribosylated in the crude extract fraction from retina control preparations, while in diabetic rats the number of retina labeled proteins and the extent of labeling are highly reduced. In the superior cervical ganglion labeling was present in 10 proteins, in diabetics it was greatly decreased. Treatment of diabetic rats with silybin, a flavonoid mono-ADP-ribosyltransferase inhibitor, did not affect hyperglycemia, but prevented the alteration of extent of protein ADP-ribosylation. These data suggest that proteins of retina and peripheral ganglia are excessively ADP-ribosylated in vivo. The effects of silybin treatment on excessive mono-ADP-ribosylation of proteins was associated with the prevention of reduction of substance P-like immunoreactivity levels, that is typical of diabetic neuropathy. In the membrane fraction of sciatic nerve Schwann cells, at least 9 proteins were ADP-ribosylated, diabetes caused a marked increase of labeling. A comparable increase involving the same proteins is triggered by chronic nerve injury and by corticosteroid treatment. Silybin treatment of diabetic rats prevented such an increase. We propose that the inhibition of excessive protein mono-ADP-ribosylation by silybin prevented the onset of diabetic neuropathy. While the effects on Schwann cells is likely indirect and secondary to the improvement of diabetic axonopathy.

IGF-I and Glycosaminoglycans Improve Peripheral Nerve Regeneration and Motor Neuron Survival in Models of Motor Neuron Disease

The discovery of agents capable of modulating neuronal survival and regeneration has been of interest to scientists since the early days of neuroscience. Recently, research into such agents has greatly increased due to their potential therapeutic use in neurodegenerative disorders [1]. Research related to nervous system regeneration following injury was strongly influenced by studies of Ramon Y Cajal [2] and Tello [3], and by the consolidation of the neuron theory. Tello wrote that lesioned nerves regenerate by forming sprouts which elongate, crossing the site of injury and regrowing into the distal stump up to the denervated muscle. He suggested that the processes of nerve regrowth and muscle reinnervation were promoted by some unknown substance liberated by the distal stump and/or by the denervated muscle. A tremendous advancement in this field came with the work of Levi Montalcini, Hamburgher and Cohen. Their contribution was dual: the description of neuronal death during embryonic development and the discovery of nerve growth factor [4–6]. It is now well known that at least for certain neuronal populations the process of cell death is regulated by the availability of a target-derived trophic factor. Nerve growth factor was the first of such trophic agents characterized [6]. Later it was found that the mammalian salivary gland, which corresponds to the snake venom gland, contained large amounts of nerve growth factor, and it became the most important source of the trophic factor [7]. With sufficient quantities of purified factor available, this field of research increased greatly.