Metabolic Brain Disease, Vol. 7, No. 3, 1992



Heat Shock Proteins in Brain Ischemia: Role Undefined as Yet Dr. K u s u m K u m a r 1

INTRODUCTION Heat shock proteins (HSP) have been highly conserved throughout evolution and are considered to have constitutive functions in protein synthesis as well as protection of cell in stress conditions (for reviews see Lindquist, 1986; Bienz & Pelham, 1987). They are expressed at increased levels in the brain subjected to a variety of stresses including hyperthermia (Currie and White, 1981; Nowak, 1988; Cosgrove and Brown, 1984; Miller et al., 1991), traumatic injury (Brown et al., 1989), noxious stimuli (Gonzales et a1.,1989), hypoxia (Dwyer et al., 1989) and ischemia (Nowak,1985; Dienel et a/.,1986; Kiessling et a/.,1986; Jacewicz et al., 1986; Vass et al., 1988; Nowak et al., 1990; Kumer and Madhukar, 1991). The HSPs are catergorized in three major families on the basis of molecular weight. The HSP-90 family includes proteins with molecular weight of 90 kD in mammals and 83 kD in bacteria and Drosophila (Bienz and Pelham, 1987). The HSP-70 family includes 72 kD and 73 kD proteins in mammals and 68 kD and 70 kD proteins in Drosophila. The third family includes proteins with molecular weights 15 kD - 30 kD (Bienz and Pelham 1987; Pardue, 1988). Ubiquitin, a 76 kD protein, is also considered a heat shock protein that acts jointly with other HSPs in stress responses (Morandi et a/.,1989). Of all the HSPs, it is the HSP-70 class that has been studied most in the nervous system. In normal animal brain the constitutive expression is observed throughout the brain simular to that of a Nissl stain pattern being present in large quantities in the cerebellum and hippocampus (Sprang and Brown, 1987). It is not clear whether HSPs serve as useful early markers of ischemic neuronal injury or serve as truly protective responses in reparative processes that are important for the survival of cells (Nowak, 1990). The mechanisms by which brain ischemia triggers 1 Department of Pathology, Michigan State University, A 622 E. Fee Hall, East Lansing, MI,48824.

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expression of HSP-70, how it correlates with cell injury, and whether HSP-70 expression in various regions of the brain correlates with vulnerability or resistance to ischemia are not clearly understood.

Functions of Heat Shock Proteins

Although the exact function of HSPs in not known, HSP-70 is considered to be active in translocation of proteins across membranes (Velazquez and Lindquis4 1984; Lewis and Pelham, 1985). The HSPs act as "unfoldases" and play a role in cell repair by modulating protein conformational changes through maintainance of the unfolded state needed for proteins to cross membranes (Chirico et al., 1988). HSP could, therefore, stabilize other proteins and help in protein renaturation and serve to protect cells from injury (Schlesinger, 1986; Pelham, 1982). Knock-out deletions of HSP-70 gene in prokaryotes render them incapable of surviving thermal shock. During and following heat shock, HSP-70 moves from the cytosol into the nucleus and concentrates strongly in the nucleolus where it may play an important role in repair by removing damaged nuclear ribonucleic acid protein complexes (Welch and Feramesico, 1984). It is also considered to be involved in normal development and cellular differentiation (Bensaude et al., 1983). Early evidence that heat shock response is protective comes from experiments demonstrating that cells subjected to modest warming survive an otherwise lethal heat shock (Lindquist, 1986). Intracellular microinjections of monoclonal antibodies to HSP-70 render fibroblasts incapable of surviving brief heat shock (Riabowal et al., 1988). The classic heat shock response is characterized by immediate (within 10 min) transcription of the HSP genes, nearly complete dissagregation of polysomes, a precipitous decline in total protein synthesis, and condensation of nuclear chromatin. Ultrastructural nuclear changes, e.g., clumping and margination of nuclear chromatin, are similar to those observed in postischemic brain (Jenkins et al., 1981;Kumar et al., 1987). HSP expression in non-neural systems has been reviewed recently by Gething and Sambrook (1992); the present review deals specically with HSPs and brain ischemia.

Heat Shock Proteins and Brain Ischemia

Although transient ischemia leads to a decrease in overall protein synthesis (Munekata et al., 1987; Dienel et al.,1985,Nowak et al., 1985 Bodsch et al., 1986), there occurs an

induction of a set of heat shock proteins in the brain that reaches a maximum after 8 h of recirculation (Nowak et al., 1985; Dienel et al.,1986; Kiessling et al., 1986; Jacewicz et al., 1986; Vass et a/.,1988; Nowak et al., 1990; Nowak et al, 1990; Nowak, 1991; Kumar and Madhukar, 1991). Transient ischemia produced by bilateral carotid occlusion in the gerbil results in 5-10 fold increase in inducible HSP 70 sequences in the brain (as determined in whole brain extract) which peaks at 6 h recirculation and remains above normal control at 24 h (Nowak et al., 1990; Kumar and Madhukar, 1991). Cerebral ischemia in the rat model of 4-vessel

HSP in Postischemic Brain


occlusion also revealed an early induction of HSP-70 occuring after 3 h of recirculation, and its synthesis varied in different regions examined (Kiessling et al., 1986). Comparing the pattern of changes in synthesis of HSP-70 with the pattern of neuronal injury in this model (Pulsinelli et al., 1982), it appears that the persistent synthesis of HSP-70 in the hippocampus correlates with progressive neuronal injury (Kiessling et al., 1986). In animal models of focal cerebral ischemia the expression of HSP-70 mRNA is prolonged in regions undergoing injury, but is transient in surrounding regions that are destined to recover (Welsh et al., 1992). The HSP-70 mRNA is expressed in a wider distribution than the expected size of the infarct (Welsh et al., 1992). Transient occlusion of the proximal middle cerebral artery also revealed expression of HSP-70 within multiple foci (Sharp et al., 1991). However, no attempt was made to correlate the expression of HSP-70 with the extent of cellular injury in these studies. Forebrain ischemia in the gerbil leads to the expression of HSP-70 mRNA in CA1 region of the hippocampus early with persistence for at least 48 h (Nowak, 1991), i.e., until the onset of neuronal death in the same region (Kirino, 1982). In contrast, the CA3 region and dentate layer, i.e., regions known to be relatively resistant to ischemia (Kirino, 1982), show HSP-70 mRNA expression only during the first 12 hours following ischemia. Only minimal immunoreactivity for HSP-70 is demonstrable in the CA1 region in the same model (Vass et al., 1988). However, pronounced immunoreactivity is noted in the hippocampus, CA3, and dentate layer that appears only after 48 h of recirculation. Since the pronounced accumulation in CA3 region is not noted until 48 hours following ischemia (Vass et al., 1988), it is possible that HSP-70 synthesis is a response to delayed pathophysiologic events in the hippocampus rather than a direct response to ischemia itself (Brown, 1990). The expression of HSP-70 was prolonged in the CA1 region that is known to be susceptible to ischemia while the disappearance of HSP-70 expression in the same region appeared to correspond with the onset of delayed neuronal death known to occur in this region (Nowak, 1991). Therefore, HSP-70 expression may be protective in nature and that as long as its expression persists, the cells may be protected from injury. It is also possible that irreversible neuronal death may be a result of aborted recovery because of failure of the cell's stress response (Kirino et al., 1991). However, the question arises whether HSP-70 expression can really be protective even when the protein is not synthesized. The above observations have also been interpreted to indicate that the expression of HSP-70 is prolonged in regions destined to undergo cell death and that it serves as a marker of cell injury (Nowak, 1991). A few other studies also support the view that HSPs serve as markers of injury and do not provide a definite evidence of neuroprotection (Gonzales et al., 1989; Ferriero et al., 1990; Lowenstein et a/.,1990; Gonzales et al., 1991). Neurons within infarcted regions of brain clearly destined to die may or may not express HSP 72 (Gonzales et al., 1989). Therefore, it is not possible to say whether cells expressing HSP are destined to survive or die. The protective role of HSP-70 in non-neuronal systems is evident by in vitro experiments where HSP-70 seems to be critical for cell survival (Johnston and Kucey, 1988). Cells survive heat shock if they are first subjected to modest wanning during which time they express HSPs. Fibroblasts microinjected with antibodies against HSP-70 are unable to survive brief heat shock (Raibowol et al., 1988). Although there is no direct evidence that HSP induction is protective in neural systems, there are studies utilizing cultured neurons that indicate the protective nature of HSPs (Lowenstein et al.,



1991; Rordorf et al., 1991). These demonstrate that preinduction of HSPs in cultured neurons is associated with protection from glutamate-induced injury (Lowenstein et al., 1991; Rodorf et al., 1991). However, it remains to be shown whether this protection is directly related to HSPs. Brief ischemia sublethal to neurons renders hippocampal neurons more tolerant to subsequent ischemic stress (Kirino et al., 1991). The same level of brief ischemia also leads to increase in HSP-70 immunostaining which in its temporal pattern does not actually correlate with the pattern of induced tolerance (Kirino et al., 1991). It is possible that the CA1 neurons became more tolerant because the prior stress rendered them more capable of recovering protein synthesis. The presence or absence of HSP-70 (protein) synthesis may just be a reflection of overall protein synthesis; after long term ischemia that is induced without preceding brief stress, the overall protein synthesis does not recover and the HSP-70 synthesis is not activated. Repetitive hyperthermic pretreatments before ischemia in a gerbil model confer protection against neuronal death in the CA1 region of the hippocampus suggesting the protective role of the stress reaction (Kitagawa eta/., 1991). In the same study, single hyperthermic treatment led only to little protection. Hyperthermia has also been associated with protection against light damage in the rat retina (Barbe et al., 1988). Choppet al. (1991) demostrated marked HSP-72 immunoreactivity in morphologically intact neurons in CA1 and CA2 regions of the hippocampus 48 hours following the induction of transient forebrain ischemia in rat. In rat brains subjected to graded global ischemia, immunoreactivity for HSP-72 is expressed in susceptible regions after brief ischemia while the resistant regions express only after sustained ischemia (Simon et al., 1991) Gonzales et al., (1991) demonstrated that the immunoreactivity for HSP-72 in hippocampal sectors correlates with their vulnerability to ischemia. There is no concomitant report in the literature that describes the time course of HSP-70 mRNA expression by in situ hybridization and HSP-70 immunoreactivity following ischemia in the same brain. The study by Vass et al. (1988) described HSP-70 immunoreactivity, while the study by Nowak (1991) was limited to HSP-70 expression. Although these two studies were performed in similar animal models, the period of ischemia differed. The conditions of fixation and tissue processing were also different. Therefore it cannot be said with certainty that the apparent lag period betweeen the HSP-70 mRNA induction and protein synthesis (Nowak, 1991 ) is real or that it represents an artefact due to variations in fixation and tissue processing techniques in these two studies (Vass et al., 1988; Nowak, 1991). It is also possible that there are some as yet unknown factors accounting for the lack of detection of immunoreactivity in susceptible regions (Nowak, 1991). It is well known that different regions of the brain vary in their response to ischemia (Siesjo, 1981; Pulsinelli et al., 1982; Petito et al., 1987). Whether regional differences in the expression of HSP-70 in the postischemic brain correlate with vulnerability or resistance is still not clearly understood. Regional differences exist in the expression of HSP-70 in the postischemic brain correlate with vulnerability or resistance is still not clearly understood. Regional differences exist in the expression of HSP genes in the brain following hyperthermia which leads to significant induction of HSP-70 related RNAs in neurons in the cerebellum and in fiber tracts (consistent with a glial localization) throughout the brain but not in the hippocampus (Sprang and Brown, 1987). To understand the mechanism and significance of induction of stress proteins, it will be necessary to evaluate histologic

HSP in Postischemic Brain


damage, mRNA expression, and synthesis of HSP-70 in vulnerable and resistant regions of the brain adjacent sections obtained from the same brain in any model of ischemia (Nowak, 1991; Chopp et al., 1992; Welsh et al., 1992). Specific Cell Types in Brain and HSP Hyperthermia induces HSP-68 primarily in rat astrocytes and oligodendrocytes and less so in neurons in culture (Nishimura et al., 1988). In vitro studies of cerebellar cells indicate that hyperthermia induces HSP-70 mRNA expression in the cerebellar astrocytes but not in granule cells, whereas immunoreativity is present in the granule cells in vivo (Marini et al., 1990). From these studies it appears that glial cells may be the major site of HSP synthesis; however, the role of neuronal cells is not yet defined. In studies of localized trauma produced in brain, both neurons and glial cells reveal induction of HSP-70 (Brown et al., 1989). Although it appears that most of the expression of HSP-70 following ischemia occurs in major neuronal populations, emulsion coating of hybridized slides with detailed microscopic study of cells will help precisely define the cell types expressing HSP-70. Various morphological changes in endothelial cells have been characterized in postischemic brain (Dietrich et al., 1984; Kumar et al., 1987a). Intense immunostaining of endothelial ceils in damaged areas of the cortex and hippocampus has been described 12 hours following hypoxia (Ferriero et al., 1990). However, it would be of interest to further define the expression of HSP-70 in endothelial cells of the brain. Furthermore, it would be important to determine whether endothelial expression of HSP-70 differs in selectively vulnerable regions of brain in comparison to the resistant regions. Mechanisms of Induction of HSP in Brain by Ischemia The mechanism by which ischemia leads to induction of HSP-70 mRNA is not well understood. In the case of hyperthermia it has been shown that first there is activation of preexisting cytoplasmic protein which then migrates to the nucleus leading to transcription of the HSP-70 gene (Wu et al., 1987). Whether similar activation of preexisting proteins occurs in cerebral ischemia also is not known. HSP-70 was induced in regions of neocortex in which blood flow was decreased only to 40 ml/100 g/min (Jacewicz et al., 1986) suggesting that even a modest decrease in cerebral blood flow may be sufficient to cause induction of HSP-70 mRNA. The precise degree and duration of ischemia required for induction of HSP-70 in brain remains unclear. From studies in a global ischemia model, it appears that 2 min of ischemia is associated with increased expression of HSP-70 in the hippocampus (Nowak and Osborne, 1991). Therefore, it is likely that only a brief energy failure may trigger HSP-70 gene activation. Whether it is a cause and effect relationship is not yet clearly understood. Future Perspectives Induction of HSP-70 in the brain in response to a wide range of stresses or traumas indicates that HSP-70 may play a protective role in biological tissues. However, the mechanisms that actually turn on the HSP-70 genes are not understood. Therefore various



steps involved in the activation of HSP-70 gene need to be elucidated. Futhermore, since various types of stresses induce HSP-70, it would be important to delineate whether the mechanism of induction is common in all cases (Brown, 1990). It is well known that all regions of the brain are not equally susceptable to ischemia (Kirino, 1982). Whether induction of HSP-70 in a particular region of brain actually influences its ability to survive injury still needs to be determined. If induction of HSP-70 is truly a protective response and not just a "reactive" or "secondary" event, it might even be possible to explore new avenues by which nerve cells may be induced to activate HSP-70 gene to promote repair mechanisms in neurons or to make them more resistant (Brown, 1990). It still needs to be explored whether microinjections of HSP into cells will provide new approaches for prevention of neuronal injury or for repair following trauma (Brown, 1990). The question of difference in the expression of HSP-70 in vulnerable and resistant regions of the brain following ischemia and reperfusion, and the mechanisms involved still needs to be addressed fully. Concomitant studies of in situ hybridization to detect mRNA expression of HSP-70, immunocytochemistry to detect synthesis of the protein, and morphometric studies to detect histologic neuronal damage need to be performed in the same brain for a clear understanding of the expression of HSP-70 in vulnerable vs. resistant regions of the brain. There are differences in the pattern of expression of HSP-70 in neurons and glial cells in response to hyperthermia (Nishimura et al., 1988). Although differences in activation of HSP-70 genes in various brain cell types also hold true in response to ischemia with most of the expression of HSP-70 occuring in major neuronal populations, emulsion coating of hybridized slides with detailed microscopic study of cells will further help precisely define the cell types expressing HSP-70. There is evidence of immunoreactivity in endothelial cells in injured regions of the brain; however, it would be important to further characterize the HSP-70 expression in endothelial cells and determine whether endothelial expression of HSP-70 differs in selectively vulnerable regions of the brain in comparison to resistant regions. Thus, HSP-70 mRNA expression appears to be an early biochemical marker identifying vulnerable cells and may be used in the evaluation of therapuetic modalities. An important question that still needs to be addressed is whether induction of HSP-70 in a particular brain region correlates with protection and whether induction of the gene or transport of the protein into the brain cells will somehow facilitate recovery from injury (Brown, 1990). ACKNOWLEDGMENTS This work was supported by a research grant from National Institutes of Health (#26489). The author gratefully acknowledges Dr. Adalbert Koesmer for reviewing the manuscript. REFERENCES

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HSP in Postischemic Brain


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Heat shock proteins in brain ischemia: role undefined as yet.

Metabolic Brain Disease, Vol. 7, No. 3, 1992 Review Article Heat Shock Proteins in Brain Ischemia: Role Undefined as Yet Dr. K u s u m K u m a r 1...
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