Induced Tolerance to Ischemia in Gerbil Hippocampal Neurons

Abstract

Summary: Brief ischemia induced tolerance to subse quent ischemia in the hippocampal neurons. Male Mon golian gerbils were subjected to 2 min of ischemia in an awake condition. This ischemic insult only rarely pro duced neuronal damage in the gerbil brain. One day (n = 9), 2 days (n = 9), or 4 days (n = 10) following the first brief ischemia, the animals (double-ischemia group) were subjected to the second ischemia for 5 min. The single ischemia group received a sham procedure instead of the first ischemia and was identically subjected to the second ischemia I day (n = 9), 2 days (n = 10), and 4 days (n = 13) following the sham procedure. One week following the second ischemia, all gerbils were perfusion fixed and the neuronal density in the hippocampal CA I sector was measured. In double-ischemia groups, the neuronal denThe brain is particularly vulnerable to distur bances of energy metabolism, such as ischemia, an oxia, hypoglycemia, or status epilepticus (Auer and Siesj6, 1988; Siesj6 and Bengtsson, 1989). Even a brief episode of ischemia destroys certain groups of ischemia-sensitive neurons. These selectively vul nerable neurons are found in the hippocampal CA 1 sector, in the dorsolateral striatum, in certain layers of the cerebral cortex, and in the cerebellar cortex (Wieloch, 1985). Among these vulnerable cells in the brain, hippocampal CAl pyramidal cells have been the most extensively studied. Following brief ischemia, CA 1 pyramidal cells recover energy me tabolism (Pulsinelli and Duffy, 1983; Arai et a!. , 1986) and electrophysiological activity (Suzuki et a!., 1983). The fine structure of CA 1 pyramidal cells is maintained well until they are disintegrated 3 or 4Received July 18 , 1990 ; revised August 27 , 1990 ; accepted Au gust 31 , 1990 .Ad dress correspondence and reprint requests to Dr . T . Kirino at Department of Neurosurgery , Teikyo University School of Medicine , 7-3-\ Kaga , It abashi-ku , Tokyo 173 , Japan .Abbreviation used: hsp70 , 70-kDa heat-shock protein . 299sity per I-mm length of the pyramidal cell layer was 103.4 ± 93. 1 (SD) in the I-day subgroup, 125. 6 ± 64. 2 in the 2-day subgroup, and 176. 2 ± 93.7 in the 4-day subgroup, while the density in normal gerbils was 254.7 ± 18.6. The average neuronal density in the single-ischemia group was much lower than that in the double-ischemia group (whole control group: 10. 9 ± 27.4). Immunostaining using monoclonal antibody raised against 70-kDa heat-shock protein revealed an increase in 70-kDa heat-shock protein in the CAl area following 2 min of ischemia. Very brief ischemia induces heat-shock proteins and, presumably, thereby renders neurons more tolerant to subsequent metabolic stress.

Attenuation of Ischemic Brain EDEMA and Cerebrovascular Injury after Ischemic Preconditioning in the Rat

“…As mentioned above, HSP70 itself has been suggested to be involved in the neuroprotective effect of IPC (Kirino et al, 1991), and a number of studies, including this study, have shown that IPC induces the production of HSP70 in neurons (Chen et al, 1996;Chen and Simon, 1997). Prolonged cerebral ischemia up-regulates HSP70 in endothelial cells in normal rats and, to a reduced extent, IPC-treated rats, as shown in the current study and previous studies (Kinouchi et al, 1993a;Lindsberg et al, 1996).…”

“…Heat shock protein 70 has been thought of both as a neuroprotective agent (Kirino et al, 1991) and as a marker of cell stress (Gonzalez et al, 1989;Wagner et al, 1999) including endothelial injury (Lindsberg et al, 1996). The reduction in the number of HSP70ir blood vessels during the permanent MCAO by previous IPC suggests reduced cerebrovascular injury or stress.…”

“…There is a prominent HSP70 induction after focal cerebral ischemia where neurons, glia, and vascular cells may all up-regulate this protein (Kinouchi et al, 1993b;Li et al, 1992;Sharp et al, 1991). Heat shock protein 70 is a molecular chaperon that has been hypothesized, along with other heat shock proteins such as HSP32 and HSP27, to be a neuroprotective agent (Kato et al, 1994;Kirino et al, 1991;Panahian et al, 1999). However, it is also a marker of cell stress and cell injury and its production is down-regulated by cell protective agents (Abe et al, 1997;Gething and Sambrook, 1992;Gonzalez et al, 1989;Sloviter and Lowenstein, 1992).…”

Adaptive Preservation of ATP and Tolerance to Hypoxia following Carotid Artery Ligation in the Immature Rat

“…Although ations in the brain parenchyma that increases the tolerance to hypoxia independent of ATP preserva tion. Thus, it has been suggested that induction of heat-shock proteins or immediate-early genes, such as c-fos, following sublethal ischemia mediates an increase in the tolerance to subsequent episodes of ischemia (Kirino et al, 1991;Glazier et al, 1994).…”

In VitroIschemic Tolerance Involves Upregulation of Glutamate Transport Partly Mediated by the TACE/ADAM17-Tumor Necrosis Factor-α Pathway

“…As possible underlying molecular mechanisms, a great variety of mediators have been postulated: induction of heat shock proteins (Kirino et al, 1991), NMDA receptors (Kato et al, 1992;Kasischke et al, 1996;Grabb and Choi, 1999), antiapoptotic factors (Shimazaki et al, 1994), interleukin-1 (Ohtsuki et al, 1996), adenosine receptors and ATP-dependent potassium channels (Heurteaux et al, 1995), superoxide dismutase (Toyoda et al, 1997), reactive oxygen species (Ravati et al, 2001), nitric oxidedependent p21 ras activation (González-Zulueta et al, 2000), metallothioneins (Trendelenburg et al, 2002), activation of vascular endothelial growth factor receptor and Akt (Wick et al, 2002), erythropoietin , and caspase-3 (McLaughlin et al, 2003). In addition, the activation of transcription factors such as nuclear factor-B has been implicated recently by several authors in the development of ischemic tolerance (Blondeau et al, 2001;Ginis et al, 2002).…”