The Role of Polyamine Metabolism in Neuronal Injury Following Cerebral Ischemia

Abstract

Stroke is the leading cause of disability and the third leading cause of death in the US, affecting more than 700,000 individuals each year. 1 Moreover, the economic toll of stroke is profound, costing more than $33 billion annually in direct health care fees and an additional $21 billion in losses secondary to present treatment method inefficacies. 1 Unfortunately there are few effective stroke therapies currently available.Cell death in stroke is potentiated through a cascade of cytotoxins. In focal cerebral ischemia, cytotoxins travel past the immediate ischemic core and cause bystander cell death in the penumbra. 2 While the ischemic core is generally believed to be unsalvageable, penumbral damage may be ameliorated if an effective intervention is instituted in a timely manner. 1 To this end, research and development of therapeutic agents have focused on preserving the ischemic penumbra and limiting secondary injury following the initial insult. ABSTRACT:Stroke is a leading cause of morbidity and mortality in the US, with secondary damage following the initial insult contributing significantly to overall poor outcome. Prior investigations have shown that the metabolism of certain polyamines such as spermine, spermidine, and putrescine are elevated in ischemic parenchyma, resulting in an increase in their metabolite concentration. Polyamine metabolites tend to be cytotoxic, leading to neuronal injury in the penumbra following stroke and expansion of the area of infarcted tissue. Although the precise mechanism is unclear, the presence of reactive aldehydes produced through polyamine metabolism, such as 3-aminopropanal and acrolein, have been shown to correlate with the incidence of cerebral vasospasm, disruption of oxidative metabolism and mitochondrial functioning, and disturbance of cellular calcium ion channels. Regulation of the polyamine metabolic pathway, therefore, may have the potential to limit injury following cerebral ischemia. To this end, we review this pathway in detail with an emphasis on clinical applicability.RÉSUMÉ: Le rôle du métabolisme de la polyamine dans le dommage neurologique dû à l'ischémie cérébrale. L'accident vasculaire cérébral (AVC) est une cause importante de morbidité et de mortalité aux États-Unis. Les dommages secondaires suite à l'accident initial contribuent significativement à l'issue défavorable. Des recherches antérieures ont démontré que le métabolisme de certaines polyamines comme la spermine, la spermidine et la putrescine est élevé dans le parenchyme ischémique, ce qui provoque une augmentation de la concentration de leurs métabolites. Les métabolites des polyamines sont généralement cytotoxiques, ce qui provoque des lésions neuronales pendant la pénombre ischémique suivant l'AVC et l'expansion de la zone infarcisée. Bien que le mécanisme précis ne soit pas clair, il a été démontré qu'il existe une corrélation entre la présence d'aldéhydes réactifs résultant du métabolisme de polyamines comme le 3-aminopropanal et l'acroléine, et l'incidence de vasospasme cérébral, l...

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

“…In addition to H 2 O 2 , SMO produces 3-aminopropanal, a byproduct that contributes to the formation of acrolein, a highly reactive aldehyde. Acrolein associated with elevated polyamine catabolism has been strongly implicated in the etiology of diseases including ischemia-reperfusion injuries, renal failure, stroke, and silent brain infarction (39)(40)(41)(42)(43)(44). Further, elevated SMO expression has been observed in inflammation-associated human diseases including gastritis (22), ulcerative colitis (23), and prostatic intraepithelial neoplasia (24).…”

LPS-induced CCL2 expression and macrophage influx into the murine central nervous system is polyamine-dependent

“…Ornithine decarboxylase (ODC) is the rate-limiting enzyme in the synthesis of all three polyamines in vivo, catalyzing the conversion of ornithine to putrescine (figure 1a) (Bistulfi et al 2009, Moinard et al 2005, Pegg, 2009). Increased CNS levels of ODC and polyamines are detected in several animal models of neurodegenerative disorders including amyotrophic lateral sclerosis, ischemia and Alzheimer's disease as well as in brain tissue from individuals with Alzheimer's disease (Clarkson et al 2004, Kim et al 2009, Morrison et al 1995, Morrison et al 1998, Virgili et al 2006). Functionally, polyamines are best characterized for their effects promoting cell proliferation during development and cancer, but they also regulate a broad array of cellular functions in both neurons and inflammatory cells (Zhang et al 2000).…”

Cerebral Microvascular Endothelial Cell Apoptosis after Ischemia: Role of Enolase-Phosphatase 1 Activation and Aci-Reductone Dioxygenase 1 Translocation

“…Cerebral ischemia initiates a cascade of cytotoxic molecules responsible for the death of neural cells as well as the damage of the blood brain barrier (BBB) at the injury site. The polyamines, such as putrescine, spermindine and spermine, are elevated in the ischemic parenchyma and contribute to ischemic brain damage via enhancing N-methy-D-aspartate receptor-mediated excitotoxicity, generating toxic aldehydes and reactive oxygen species (ROS), and disrupting oxidative metabolism and mitochondrial function (Takano et al, 2005; Kim et al, 2009). The administration of polyamine antagonists prevents the development of ischemic brain damage (Takano et al, 2005; Li et al, 2007).…”

“…A recent study shows that ENOPH1 is widely expressed in the brain and stress exposure increases ENOPH1 protein levels in brain tissue of C57BL/6J mice (Barth et al, 2014). Since ENOPH1 participates in the synthesis of polyamine indirectly via S-adenosyl methionine (SAM; Takano et al, 2005; Li et al, 2007; Kim et al, 2009; Duan et al, 2011), it is logical to speculate a role of ENOPH1 in ischemic brain injury.…”