Neuroprotective role of ornithine decarboxylase activation in transient focal cerebral ischaemia: a study using ornithine decarboxylase-overexpressing transgenic rats

Abstract

Nuclear magnetic resonance imaging (MRI) was used to study dynamics of maturation and the size of ischaemic stroke lesions in rats with greatly increased activity of ornithine decarboxylase (ODC). Syngenic rats, either with or without chronic pre-ischaemic treatment with an ODC inhibitor, alpha-difluoromethylornithine (DFMO), as well as ODC-overexpressing transgenic rats were subjected either to transient middle cerebral artery (MCA) occlusion or permanent occlusion of the cortical branch of MCA. The two models were chosen to assess the role of ODC activity in damage caused by ischaemia and reperfusion, respectively. Diffusion of water was quantified by means of the trace of the diffusion tensor (D(av) = 1/3 Trace D) to assess the extent of energy failure and cytotoxic oedema, whereas the spin-spin relaxation time (T2) was used as a quantitative indicator of irreversible damage by MRI. Exposure to transient MCA occlusion resulted in significantly smaller stroke lesions in the ODC-overexpressing transgenic (246+/-14 mm3) than in syngenic (320+/-9 mm3) or DFMO-treated (442+/-63 mm3) rats as determined 48 h after the occlusion. The differences in sizes were due to smaller lesions in the cortical tissue (transgenic vs. syngenic) or both in cortical and striatal regions (transgenic vs. DFMO-treated animals). The degree of irreversible oedema was greater in DFMO-treated rats than in syngenic or transgenic animals indicating accelerated development of a permanent damage in the absence of ODC induction. Cortical infarct following permanent MCA occlusion developed faster in the DFMO-treated than in syngenic or transgenic rats as the lesion sizes at 10 h were 26.2+/-4.3 mm3, 14.2+/-2.3 mm3 and 12.3+/-1.9 mm3, respectively. However, the stroke volumes by 48 h were not statistically different in the three animal groups. The present data demonstrate that ODC activation is an endogenous neuroprotective measure in transient cerebral ischaemia.

Elevated N1‐Acetylspermidine Levels in Gerbil and Rat Brains After CNS Injury

“…On the other hand, ODC activation and putrescine accumulation showed either no effect or neuroprotection in transient focal cerebral ischemia (Keinanen et al, 1997;Lukkarinen et al, 1997Lukkarinen et al, , 1998. Previous work from our laboratory has shown induction of ODC and subsequent alterations in polyamine metabolism, particularly an increase in putrescine levels, to be an important factor in bloodbrain barrier dysfunction and the development of vasogenic edema after CNS injury (Dempsey et al, 1991;Kindy et al, 1994;Rao et al, 1995Rao et al, , 1997Başkaya et al, 1997b,c).…”

“…Previous work from our laboratory has shown induction of ODC and subsequent alterations in polyamine metabolism, particularly an increase in putrescine levels, to be an important factor in bloodbrain barrier dysfunction and the development of vasogenic edema after CNS injury (Dempsey et al, 1991;Kindy et al, 1994;Rao et al, 1995Rao et al, , 1997Başkaya et al, 1997b,c). Inhibition of ODC by ␣-difluoromethylornithine either protected the brain from ischemic damage (Schmitz et al, 1993;Kindy et al, 1994) or enhanced the infarct volume in focal cerebral ischemia (Lukkarinen et al, 1998).…”

Effect of citicoline on ischemic lesions as measured by diffusion‐weighted magnetic resonance imaging

“…A hyperacute lesion seen with DWI does not necessarily indicate infarction, because early cellular changes of ischemia (eg, cytotoxic edema) may potentially be reversed and lesion growth may be attenuated by reperfusion or neuroprotective drugs. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Human studies of stroke with DWI and perfusion MRI have confirmed the ability of these methodologies to detect early ischemic lesions. 40 -47 Correlations of initial lesion volume by DWI to final infarct size on T2-weighted MRI have been observed, as have correlations of acute lesion volumes by DWI and chronic lesion volumes by T2-weighted imaging to scores of stroke clinical severity scales.…”

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

“…Polyamine biosynthesis is regulated by the activities of ornithine and S-adenosylmethionine decarboxylases. Overexpression of ornithine decarboxylase in transgenic rodents affected spermatogenesis (1,2), rendered animals more resistant to chemically or electrically induced seizure activity (3) and to ischemic insults (4), and enhanced skin papilloma formation (5). However, the activation of polyamine biosynthesis caused by overexpression of ornithine decarboxylase did not result in enhanced accumulation of the higher polyamines spermidine and spermine.…”