Features of the Trophic Action of Polyamines

Abstract In spite of their abundance, the function of polyamines in the adult nervous system remains enigmatic. It is postulated that after trauma, the induction of polyamine metabolism (i.e. the polyamine response), which is inherently transient, is an integral part of a protective biochemical program that is essential for neuronal survival. Several functions ascribed to polyamines may assume importance in cellular defense. Thus, regulation of the ionic environment, modulation of signal pathways, control of cellular Ca2+ homeostasis, inhibition of lipid peroxidation and interaction with nucleic acids are all putative sites for polyamine action. During maturation, the CNS, unlike the peripheral nervous system, undergoes changes which result in the expression of an incomplete polyamine response after trauma. This may be due to an altered pattern of gene expression, and/or restrictive compartmentalization of the polyamines and their metabolizing enzymes. Induction of this partial polyamine response after injury results in a sustained accumulation of putrescine, which by itself may be harmful, without the concomitant increase in spermidine and spermine. Administration of exogenous polyamines after trauma exerts a neuroprotective effect. Exogenous polyamines are postulated to gain access into cells via an induced uptake system after trauma and function similarly to newly synthesized polyamines. Besides the injured neurons themselves, tissues which are connected or associated with these neurons may be potential targets where polyamines could act to stimulate neurotrophic factor production. The natural polyamines (PAs) spermine [NH2(CH2)3NH(CH2)4NH-(CH2)3N H2], spermidine [NH2(CH2)4NH(CH2)3NH2] and putrescine [NH2(CH2)4NH2] are low molecular weight, aliphatic molecules that are positively charged at physiological pH values. 77 They are widely distributed in living organisms, from bacteria to humans and can reach very high intracellular concentrations (in the millimolar range). 77 Dividing cells make large and rapid changes in PA biosynthesis and the depletion of PA leads to retardation of cell proliferation and even to cell death. 37, 57 The existing evidence therefore supports the general notion that PAs are essential for cell division and growth; alas, in spite of a large volume of research, their specific role(s) in cellular functions still remains an enigma. Interestingly, PAs are found in abundance in the adult mammalian nervous system, 74 where their synthesis can be greatly stimulated in response to stressful stimuli (e.g., glucocorticoid treatment 12 and electrical stimulation 55, 65 ) or traumatic injuries (e.g., mechanical injuries, 14, 16, 21 neurotoxins 15, 62 and ischemia 56 ). In addition, pharmacological studies have shown that exogenous PAs interact directly with the nervous system to alter its functions. 74 The possibility that PA are involved in neuronal function during the response to trauma has triggered a recent spurt of research. The focus of this paper is on the proposed functions of PAs in cellular defense mechanisms, with special emphasis on central dopaminergic neurons of the basal ganglia.