Induced expression of neurotrophins in transgenic mice overexpressing ornithine decarboxylase and overproducing putrescine

Abstract

Transgenic mice overexpressing ornithine decarboxylase (ODC) were recently generated (Halmekytö et al.: Biochem Biophys Res Commun 180:262-267, 1991). The dramatic ODC overexpression resulted in a very high accumulation of the polyamine putrescine in the brain. As elevated polyamine levels in the brain are believed to be associated with neuronal damage, we studied whether enhanced putrescine accumulation in the brain of these mice affects the expression of neurotrophins and their high affinity receptors. Northern blot analysis indicated that mRNA levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) were significantly elevated about 1.5-fold in the hippocampus of ODC transgenic mice as compared with control animals. The levels of BDNF, NGF and NT-3 mRNA were also elevated in the kidneys of the transgenic mice. In eight other tissues examined there were no significant differences. The expression pattern of BDNF mRNA and of trkB and trkC (high affinity receptors for BDNF and NT-3 respectively) immunoreactivity in the hippocampal formation did not reveal significant differences. The induction of the expression of neurotrophins could belong to neuroprotective measures triggered by ODC overexpression.

Genetic approaches to the cellular functions of polyamines in mammals

“…Taken together, these results suggest that endogenous putrescine may play a physiologically relevant role at the NMDA receptor as these receptors have a well documented role in the induction of seizure activity [63] and mediating spatial encoding [64]. The finding indicating that the transcript levels of several neurotrophins were elevated in the brain of the transgenic animals may likewise contribute to the apparent neuroprotection [65].…”

Ornithine Decarboxylase Knockdown Exacerbates Transient Focal Cerebral Ischemia-Induced Neuronal Damage in Rat Brain

“…In fact, ODC overexpressing mice showed increased cerebral expression of neurotrophins and no histopathologic damage. These mice also showed no changes in the intracellular pH, free magnesium concentration, and hippocampal long-term potentiation (Kauppinen et al, 1992;Alhonen et al, 1995;Lukkarainen et al, 1995;Reeben et al, 1996;Pussinen et al, 1998). High concentrations of polyamines are also essential for the growth and development of neurons during healthy brain development and under cell culture conditions (Seiler et al, 1984;Slotkin and Bartolome, 1986).…”

Distribution Patterns of Ornithine Decarboxylase in Cells and Tissues: Facts, Problems, and Postulates

“…In addition, polyamines have deleterious effects on nerve cells by interactions with the N -methyld -aspartate (NMDA) receptor, which contains specific recognition sites for polyamines (Williams et al 1991). However, recent studies support the idea that ODC activation and polyamine accumulation are attempts to protect or repair neurons during brain ischemia (Reeben et al 1996;Keinanen et al 1997;Lukkarinen et al 1997Lukkarinen et al ,1998. Increased ODC immunoreactivity in glial cells has also been found after subconvulsive Koibuchi et al 1990Koibuchi et al , 1993aKoibuchi et al ,1993bKoibuchi et al ,1995 electric and chemical stimulation of the brain (Orzi et al 1990;Bernstein and Müller 1999).…”

“…In transgenic mice that overexpress human ODC due to a ubiquitous promoter, abnormalities were found only in testis and brain (Halonen et al 1993). Targeted ODC overexpression using cell type-specific promotors had no phenotypic effects in liver (Alhonen et al 1996) and intestine (unpublished observations) but resulted in an increased frequency of papillomas in skin (Megosh et al 1995).…”

“…Alhonen L, Heikkinen S, Sinervirta R, Halmekytö M, Alakuijala P, Jänne J (1996) Rat prostate gland-a good model for demonstration of ornithine decarboxylase by immunohistochemistry. Histochem J 17:731-733 Dorn A, Müller M, Bernstein HG, Pajunen A, Jarvinen M (1987) Immunohistochemical localization of L-ornithine decarboxylase in developing rat brain.…”