Polyamines in the Developing Mouse Brain

Jasper, Thomas W.; Luttge, William G.; Benton, Thomas B.; Garnica, Adolfo D.

doi:10.1159/000112681

Cited by 13 publications

(7 citation statements)

References 12 publications

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“…These findings suggest that compounds that reduce polyamine levels during EtOH withdrawal eliminate some of the deficits associated with neonatal EtOH exposure. It is important to note that this approach is somewhat complicated considering the important role that polyamines play in CNS development (Jasper et al, 1982; Slotkin and Bartolome, 1986) and it may be that the timing of polyamine suppression in relation to EtOH withdrawal is critical. Clearly, further work is needed to assess this potential treatment approach.…”

Section: Discussionmentioning

confidence: 99%

Difluoromethylornithine (DFMO) reduces deficits in isolation-induced ultrasonic vocalizations and balance following neonatal ethanol exposure in rats

Rubin

Wellmann

Lewis

et al. 2009

Pharmacology Biochemistry and Behavior

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Neonatal ethanol (EtOH) exposure is associated with central nervous system dysfunction and neurotoxicity in rats. Increases in polyamine levels have been implicated as one underlying mechanism for some of EtOH's effects on the developing brain. In this study we addressed whether the inhibition of polyamine biosynthesis by α-difluoromethylornithine (DFMO) could reduce behavioral deficits induced by early EtOH exposure. Male and female rat pups received ethanol (6 g/kg/day EtOH i.g.), or isocaloric maltose (control) from postnatal days (PND) 1-8. On PND 8, animals were injected with either saline or DFMO (500 mg/kg, s.c.) immediately following the final neonatal treatment. Subjects were tested for isolation-induced ultrasonic vocalizations (USV) on PND 16; spontaneous activity in an open field apparatus on PND 20 and 21; and balance on PND 31. Animals exposed to EtOH neonatally displayed an increased latency to the first USV and reduced frequencies of USV, hyperactivity and preference for the center of the open field and poorer balance relative to controls. DFMO minimized these deficits in latency to the first USV and balance. These data provide further support that polyamines play a role in some of the functional deficits associated with EtOH exposure during early development and that reducing polyamine activity can improve outcome.

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Section: Discussionmentioning

confidence: 99%

Difluoromethylornithine (DFMO) reduces deficits in isolation-induced ultrasonic vocalizations and balance following neonatal ethanol exposure in rats

Rubin

Wellmann

Lewis

et al. 2009

Pharmacology Biochemistry and Behavior

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“…Developmental alterations of brain polyamine synthesis have been studied by different groups (Bartolome et al, 1985;Bell et al, 1986;Gilad and Kopkin, 1979;Jasper et al, 1982;Laitinen et al, 1982;Shaskan et al, 1973;Slotkin and Bartolome, 1986;Slotkin et al, 1982Slotkin et al, , 1984a. At the time of birth, polyamine synthesis is sharply activated within the forebrain: In the mouse brain at birth, ODC activity and putrescine levels are about 75 and 25 times higher than adult values, respectively, whereas spermidine and spermine levels are considerably less affected.…”

Section: Development Of the Brainmentioning

confidence: 99%

Polyamine metabolism in different pathological states of the brain

Paschen

1992

Molecular and Chemical Neuropathology

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Biosynthesis of the polyamines spermidine and spermine and their precursor putrescine is controlled by the activity of the two key enzymes ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC). In the adult brain, polyamine synthesis is activated by a variety of physiological and pathological stimuli, resulting most prominently in an increase in ODC activity and putrescine levels. The sharp rise in putrescine levels observed following severe cellular stress is most probably the result of an increase in ODC activity and decrease in SAMDC activity or an activation of the interconversion of spermidine into putrescine via the enzymes spermidine N-acetyltransferase and polyamine oxidase. Spermidine and spermine levels are usually less affected by stress and are reduced in severely injured areas. Changes of polyamine synthesis and metabolism are most pronounced in those pathological conditions that induce cell injury, such as severe metabolic stress, exposure to neurotoxins or seizure. Putrescine levels correlate closely with the density of cell necrosis. Because of the close relationship between the extent of post-stress changes in polyamine metabolism and density of cellular injury, it has been suggested that polyamines play a role in the manifestation of structural defects. Four different mechanisms of polyamine-dependent cell injury are plausible: (1) an overactivation of calcium fluxes and neurotransmitter release in areas with an overshoot in putrescine formation; (2) disturbances of the calcium homeostasis resulting from an impairment of the calcium buffering capacity of mitochondria in regions in which spermine levels are reduced; (3) an overactivation of the NMDA receptor complex caused by a release of polyamines into the extracellular space during ischemia or after ischemia and prolonged recirculation in the tissue surrounding severely damaged areas; (4) an overproduction of hydrogen peroxide resulting from an activation of the interconversion of spermidine into putrescine via the enzymes spermidine N-acetyltransferase and polyamine oxidase. Insofar as a sharp activation of polyamine synthesis is a common response to a variety of physiological and pathological stimuli, studying stress-induced changes in polyamine synthesis and metabolism may help to elucidate the molecular mechanisms involved in the development of cell injury induced by severe stress.

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“…Another potential source of CaSR activation may be from polyamines. Polyamines such as spermine and spermidine are potent agonists of the CaSR and polyamine concentrations are elevated during postnatal cerebellar development and then subsequently decline to adult levels (Jasper et al, 1982 ). The period of increased polyamines corresponds to the peak period of CaSR expression and GCP migration.…”

Section: The Casr and Integrins In The Developing Cnsmentioning

confidence: 99%

The Calcium-Sensing Receptor and Integrins in Cellular Differentiation and Migration

Tharmalingam

Hampson

2016

Front. Physiol.

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The calcium-sensing receptor (CaSR) is a widely expressed homodimeric G-protein coupled receptor structurally related to the metabotropic glutamate receptors and GPRC6A. In addition to its well characterized role in maintaining calcium homeostasis and regulating parathyroid hormone release, evidence has accumulated linking the CaSR with cellular differentiation and migration, brain development, stem cell engraftment, wound healing, and tumor growth and metastasis. Elevated expression of the CaSR in aggressive metastatic tumors has been suggested as a potential novel prognostic marker for predicting metastasis, especially to bone tissue where extracellular calcium concentrations may be sufficiently high to activate the receptor. Recent evidence supports a model whereby CaSR-mediated activation of integrins promotes cellular migration. Integrins are single transmembrane spanning heterodimeric adhesion receptors that mediate cell migration by binding to extracellular matrix proteins. The CaSR has been shown to form signaling complexes with the integrins to facilitate both the movement and differentiation of cells, such as neurons during normal brain development and tumor cells under pathological circumstances. Thus, CaSR/integrin complexes may function as a universal cell migration or homing complex. Manipulation of this complex may be of potential interest for treating metastatic cancers, and for developmental disorders pertaining to aberrant neuronal migration.

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Polyamines in the Developing Mouse Brain

Cited by 13 publications

References 12 publications

Difluoromethylornithine (DFMO) reduces deficits in isolation-induced ultrasonic vocalizations and balance following neonatal ethanol exposure in rats

Difluoromethylornithine (DFMO) reduces deficits in isolation-induced ultrasonic vocalizations and balance following neonatal ethanol exposure in rats

Polyamine metabolism in different pathological states of the brain

The Calcium-Sensing Receptor and Integrins in Cellular Differentiation and Migration

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