Tricyclic antidepressants and the incidence of certain cancers: a study using the GPRD.

BACKGROUND: Several studies suggest links between cancer and tricyclic antidepressant use. METHODS: A case-control study using the General Practice Research Database examined whether previous tricyclic usage was associated with reduced incidence of brain (with glioma as a sub-category), breast, colorectal, lung and prostate cancers. Conditional logistic regression adjusted for age, gender, general practice, depression, smoking, body mass index, alcohol use and non-steroidal anti-inflammatory drug use. RESULTS: A total of 31 953 cancers were identified, each matched with up to two controls. We found a statistically significant reduction in tricyclic prescriptions compared with controls in glioma (odds ratio (OR) =0.59, 95% confidence interval (CI)=0.42-0.81) and colorectal cancer patients (OR=0.84, CI=0.75-0.94). These effects were dose-dependent (P-values for trend, glioma=0.0005, colorectal=0.001) and time-dependant (P-values for trend glioma=0.0005, colorectal=0.0086). The effects were cancer-type specific, with lung, breast and prostate cancers largely unaffected by antidepressant use. CONCLUSION: The biologically plausible, specific and dose- and time-dependant inverse association that we have found suggests that tricyclics may have potential for prevention of both colorectal cancer and glioma.

The effects of antidepressants on mitochondrial function in a model cell system and isolated mitochondria.

The in vitro effects of antidepressant drugs on mitochondrial function were investigated in a CHOß(2)SPAP cell line used previously to determine the effects of antidepressants on gene transcription (Abdel-Razaq et al., Biochem Pharmacol 73:1995-2003, 2007) and in rat heart isolated mitochondria. Apoptotic effects of clomipramine (CLOM), desipramine (DMI) and of norfluoxetine (NORF, the active metabolite of fluoxetine), on cellular viability were indicated by morphological changes and concentration-dependent increases in caspase-3 activity in CHO cells after 18 h exposure to CLOM, DMI and NORF. However, tianeptine (TIAN) was without effect. CLOM and NORF both reduced integrated mitochondrial function as shown by marked reductions in membrane potential (MMP) in mitochondria isolated from rat hearts. DMI also showed a similar but smaller effect, whereas, TIAN did not elicit any significant change in MMP. Moreover, micromolar concentrations of CLOM, DMI and NORF caused significant inhibitions of the activities of mitochondrial complexes (I, II/III and IV). The inhibitory effects on complex IV activity were most marked. TIAN inhibited only complex I activity at concentrations in excess of 20 µM. The observed inhibitory effects of antidepressants on the mitochondrial complexes were accompanied by a significant decrease in the mitochondrial state-3 respiration at concentrations above 10 µM. The results demonstrate that the apoptotic cell death observed in antidepressant-treated cells could be due to disruption of mitochondrial function resulting from multiple inhibition of mitochondrial enzyme complexes. The possibility that antimitochondrial actions of antidepressants could provide a potentially protective pre-conditioning effect is discussed.

The effects of antidepressants on cyclic AMP-response element-driven gene transcription in a model cell system.

The effects of the antidepressant drugs clomipramine (CLOM), desipramine (DMI), tianeptine (TIAN) and of norfluoxetine (NORF, the active metabolite of fluoxetine), were investigated in CHO cells expressing human beta2 adrenoceptors and a secreted placental alkaline phosphatase (SPAP) reporter gene to determine their actions on cyclic AMP-driven gene transcription. After 18 h of exposure, CLOM, DMI and NORF, but not TIAN, had biphasic effects on 1 microM isoprenaline-stimulated SPAP fsproduction with concentrations between 10 nM and 1 microM enhancing the maximal (E(max)) SPAP response, without changing EC50 values, but higher concentrations produced marked inhibitory effects. At nanomolar concentrations, CLOM and DMI increased expression of phospho-CREB (cyclic AMP response element binding protein). NORF was less effective but did significantly increase phospho-CREB at a concentration of 200 nM. TIAN had no effect. None of the antidepressants had any effect on CREB expression, nor on the accumulation of cyclic AMP. After prolonged exposure (7-21 days) to a low concentration (200 nM) of the antidepressants, the enhanced E(max) values for SPAP production evident after 18 h were not maintained but CLOM and DMI induced a significant leftward shift in the isoprenaline EC50 after a 7-day period of treatment and this was sustained at the 21 day time point. TIAN did not produce any significant changes. The results demonstrate that, in vitro, some but not all antidepressants can modify gene transcription via monoamine and cyclic AMP-independent mechanisms. The in vivo adaptive responses to TIAN probably involve alterations in different gene sets to those affected by other antidepressants.

The effects of desmethylimipramine on cyclic AMP-stimulated gene transcription in a model cell system.

The present study utilised an in vitro cell model of the cAMP signalling pathway to investigate the actions of desipramine (DMI) and other psychoactive agents on cAMP-driven gene transcription. The model comprised CHObeta2 SPAP cells; Chinese hamster ovary cells expressing human beta2 adrenoceptors and a secreted placental alkaline phosphatase (SPAP) reporter gene with multiple cAMP response elements (CREs) in its promoter region. SPAP assays showed DMI to inhibit isoprenaline or forskolin-enhanced gene transcription in a time and concentration-dependent manner (IC50=16.6+/-2.0 microM after 18 h). This effect of DMI was not dependent upon activity at the levels of the beta2 receptor, cAMP accumulation or phosphorylation of the transcription factor, cAMP response element binding protein (CREB). The inhibitory effects were maintained in the presence of DMI for at least 3 weeks and were mimicked by exposure to norfluoxetine (the major metabolite of fluoxetine; IC50=7.2+/-1.8 microM) and the neuroleptics, chlorpromazine and clozapine, all at a concentration of 10 microM. Amphetamine (10 microM, 18 h) enhanced SPAP gene transcription. Ca2+ imaging experiments ruled out an inhibitory effect of DMI on Ca2+ influx as concluded by previous studies. The results suggest a molecular target for DMI that lies downstream of CREB phosphorylation. Whether the inhibitory action of DMI is common to naturally expressed CRE-driven genes involved in adaptive responses to antidepressants in vivo remains to be determined.

Chlorimipramine: a novel anticancer agent with a mitochondrial target.

Mitochondria have been suggested to be a potential intracellular target for cancer chemotherapy. In this report, we demonstrate the ability of the tricyclic antidepressant chlorimipramine to kill human glioma cells in vitro by a molecular mechanism resulting in an increase in caspase 3 activity following inhibition of glioma oxygen consumption. Studies with isolated rat mitochondria showed that chlorimipramine specifically inhibited mitochondrial complex III activity, which causes decreased mitochondrial membrane potential as well as mitochondrial swelling and vacuolation. The use of chlorimipramine in human as an effective, non-toxic cancer therapeutic having a strong selectivity between cancer cells and normal cells on the basis of their mitochondrial function is discussed.

Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevity.

It is becoming increasingly evident that the mitochondrial genome may play a key role in neurodegenerative diseases. Mitochondrial dysfunction is characteristic of several neurodegenerative disorders, and evidence for mitochondria being a site of damage in neurodegenerative disorders is partially based on decreases in respiratory chain complex activities in Parkinson's disease, Alzheimer's disease, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant balance perturbation, are thought to underlie defects in energy metabolism and induce cellular degeneration. Efficient functioning of maintenance and repair process seems to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of genes termed vitagenes. A promising approach for the identification of critical gerontogenic processes is represented by the hormesis-like positive effect of stress. In the present review, we discuss the role of energy thresholds in brain mitochondria and their implications in neurodegeneration. We then review the evidence for the role of oxidative stress in modulating the effects of mitochondrial DNA mutations on brain age-related disorders and also discuss new approaches for investigating the mechanisms of lifetime survival and longevity.

Effects of acetyl-L-carnitine on the formation of fatty acid ethyl esters in brain and peripheral organs after short-term ethanol administration in rat.

Increasing evidence suggests that Fatty acid ethyl esters (FAEE) play a central role in ethanol induced organ damage. In the current study we measured FAEE formation in rats after short-term oral administration of ethanol, in the presence and absence of pre-treatment with acetyl-L-carnitine. Ethanol treatment caused a significant increase in the levels of FAEE, particularly in the brain and heart, but also in the kidney and liver. Increases in FAEE were associated with a significant increase in FAEE synthase activity, GSH transferase activity, and lipid hydroperoxide levels. Pretreatment with acetyl-L-carnitine resulted in a significant reduction of FAEE accumulation, decrease in FAEE synthase and GSH transferase activities, and lipid hydroperoxide levels. Administration of acetyl-L-carnitine greatly reduced the metabolic abnormalities due to non-oxidative ethanol metabolism, through an increment in lipid metabolism/turnover and by the modulation of the activities of enzymes associated with FAEE synthesis. These results suggest a potentially important pharmacological role for acetyl-L-carnitine in the prevention of alcohol-induced cellular damage.

Induction of heat shock protein synthesis in human skin fibroblasts in response to oxidative stress: regulation by a natural antioxidant from rosemary extract.

Reactive oxygen species have been implicated in the pathogenesis of the severe connective tissue damage present in several photodermatologic disorders, including drug-induced phototoxicity, porphyrias and photoaging. Oxidative stress has been shown to alter the expression of mammalian antioxidant enzymes and to enhance numerous transcription factors, including nuclear factor-kappa B, stress-activated protein kinase and heat shock factor. The latter represents the transcription factor for the synthesis of cytoprotective proteins called heat shock proteins. In this study, we investigated the role of oxidative stress and sulfdryl (SH) groups in the induction of HSP70 in human skin fibroblasts and the effect of antioxidants. We found that significant HSP70 induction occurred after exposure to HOOH and this was associated with marked perturbation in protein and nonprotein SH groups and with a considerable increase in protein carbonyl levels. Treatment with a natural antioxidant from rosemary extract provided notable protection against stress-induced modifications of cellular SH and carbonyl content, maintaining functional levels of cytoprotective heat shock protein 70. Our results point to the possible involvement of redox mechanisms in the heat shock signal transduction pathway, which may play an important regulatory role in the genetic mechanisms of tolerance to oxidative stress. Exogenous supplementation of an antioxidant hydrophilic extract from rosemary could have cosmetic benefits and may represent an efficient tool to minimize free radical-induced skin damage.

Heat stress contributes to the enhancement of cardiac mitochondrial complex activity.

Hyperthermic stress is known to protect against myocardial dysfunction after ischemia-reperfusion injury. It is unclear however, what energetic mechanisms are affected by the molecular adaptation to heat stress. We hypothesized that mild hyperthermic stress can increase mitochondrial respiratory enzyme activity, affording protection to mitochondrial energetics during prolonged cardiac preservation for transplantation. Rat hearts were excised after heat-stress or sham treatment and subjected to cold cardioplegic arrest and ischemia followed by reperfusion in an ex vivo perfusion system. Cardiac function, mitochondrial respiratory, and complex activities were assessed before and after ischemia. Heat shock protein (Hsp 32, 60, and 72) expression was increased in heat-stressed hearts. This was associated with increased mitochondrial complex activities in heat-stress versus sham-treated groups for complex I-V. During reperfusion, higher complex activities and respiratory control ratios were observed in heat-stressed versus sham-treated groups. Recovery of ventricular function was improved in heat-stressed hearts. Furthermore, mitochondria in reperfused heat-stressed myocardium exhibited intact membranes with packed, parallel, lamellar cristae, whereas in sham-treated myocardium, mitochondria were severely disrupted. This study provides the first evidence of heat-stress-mediated enhancement of mitochondrial energetic capacity. This is associated with increased tolerance to ischemia-reperfusion injury. Protection by heat stress against myocardial dysfunction may be partially due to enhancement of mitochondrial energetics.

Activation of murine microglial cell lines by lipopolysaccharide and interferon-gamma causes NO-mediated decreases in mitochondrial and cellular function.

Activation of murine microglial and macrophage cell lines with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) resulted in the induction of the inducible form of nitric oxide synthase (NOS) and the release of micromolar amounts of NO into the surrounding medium. The synthesis of NO was associated with increased cellular membrane damage as assessed by trypan blue dye exclusion and the leakage of lactate dehydrogenase into the cell culture medium. However, the synthesis and release of cytokines was largely unaffected. NO-mediated cell damage was also accompanied by a marked decrease in the intracellular levels of reduced glutathione and ATP. In addition, significant inhibition of mitochondrial respiratory chain enzyme activities was seen following cellular activation. However, citrate synthase activity (a mitochondrial matrix enzyme) was not detectable in the extracellular supernatants, suggesting preservation of the integrity of the mitochondrial inner membrane following activation. These effects were largely prevented by the addition of the NOS inhibitor, N-guanidino monomethyl L-arginine during the activation period. Our observations demonstrate that induction of NOS activity in microglia results in damage to the plasma membrane leading to a loss of glutathione, complex-specific inhibition of the mitochondrial electron transport chain and depletion of cellular ATP. Our data suggest that pharmacological modulation of NOS activity in activated microglia in vivo may prevent cellular damage to bystander cells such as neurons, astrocytes and oligodendrocytes, as well as to microglia themselves.

Regulation of heat shock protein synthesis in human skin fibroblasts in response to oxidative stress: role of vitamin E.

Skin plays an important role in protection against oxidative stressors such as ultraviolet radiation, ozone and chemicals. Chronic sun exposure causes degenerative changes in the skin that are recognized as photoaging. Oxidative stress has been shown to alter the expression of mammalian antioxidant enzymes as well as to enhance numerous transcription factors, including nuclear factor kappaB, stress-activated protein kinase and heat shock factor This latter is the transcription factor for the synthesis of heat shock proteins, which have been known to protect against a wide variety of toxic conditions, including extreme temperatures, oxidative stress and cytotoxic drugs. In this study we investigated the role of oxidative stress in the induction of heat shock protein (HSP) 70 in human skin fibroblasts and the effect of vitamin E. We found that significant HSP70 induction occurred after exposure to HOOH and that this was associated with a significant perturbation in protein and nonprotein sulfhydryl groups, and with a significant increase in protein carbonyl levels. Treatment with vitamin E conferred significant protection against stress-induced modifications of cellular sulfhydryl and carbonyl content, while maintaining functional levels of cytoprotective HSP70. Our results point to the possible involvement of redox mechanisms in the heat shock signal transduction pathway, which may play an important regulatory role in the genetic mechanisms of tolerance to oxidative stress. Exogenous antioxidant supplementation with vitamin E could have cosmetic benefits and may be an efficient tool to mitigate the consequences of free radical-induced skin damage.

Nitric-oxide-induced inhibition of mitochondrial complexes following aglycaemic hypoxia in neonatal cortical rat brain slices.

The effect of aglycaemic hypoxia (AH) on the activity of the mitochondrial respiratory chain complexes was measured in superfused neonatal cortical brain slices. After 30 min AH, there were no significant changes in the activities of complex I, II-III and IV or citrate synthase compared to controls. Following 30 min AH and a 30-min reperfusion period (with oxygen and glucose), the activities of complex II-III and complex IV were significantly reduced (by 25 and 17%, respectively). These reductions in enzyme activity were not abrogated by removing external calcium prior to and throughout AH, but could be reversed by the presence of the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine during these periods. These data suggest that NO or an NO-derived species is involved in the decreases in mitochondrial enzyme activities observed after AH

NO synthase and NO-dependent signal pathways in brain aging and neurodegenerative disorders: the role of oxidant/antioxidant balance.

Nitric oxide and other reactive nitrogen species appear to play several crucial roles in the brain. These include physiological processes such as neuromodulation, neurotransmission and synaptic plasticity, and pathological processes such as neurodegeneration and neuroinflammation. There is increasing evidence that glial cells in the central nervous system can produce nitric oxide in vivo in response to stimulation by cytokines and that this production is mediated by the inducible isoform of nitric oxide synthase. Although the etiology and pathogenesis of the major neurodegenerative and neuroinflammatory disorders (Alzheimer's disease, amyothrophic lateral sclerosis, Parkinson's disease, Huntington's disease and multiple sclerosis) are unknown, numerous recent studies strongly suggest that reactive nitrogen species play an important role. Furthermore, these species are probably involved in brain damage following ischemia and reperfusion, Down's syndrome and mitochondrial encephalopathies. Recent evidence also indicates the importance of cytoprotective proteins such as heat shock proteins (HSPs) which appear to be critically involved in protection from nitrosative and oxidative stress. In this review, evidence for the involvement of nitrosative stress in the pathogenesis of the major neurodegenerative/ neuroinflammatory diseases and the mechanisms operating in brain as a response to imbalance in the oxidant/antioxidant status are discussed.

Characteristics of the calcium-triggered mitochondrial permeability transition in nonsynaptic brain mitochondria: effect of cyclosporin A and ubiquinone O.

The objective of the present study was to assess the capacity of nonsynaptic brain mitochondria to accumulate Ca2+ when subjected to repeated Ca2+ loads, and to explore under what conditions a mitochondrial permeability transition (MPT) pore is assembled. The effects of cyclosporin A (CsA) on Ca2+ accumulation and MPT pore assembly were compared with those obtained with ubiquinone 0 (Ubo), a quinone that is a stronger MPT blocker than CsA, when tested on muscle and liver mitochondria. When suspended in a solution containing phosphate (2 mM) and Mg2+ (1 mM), but no ATP or ADP, the brain mitochondria had a limited capacity to accumulate Ca2+ (210 nmol/mg of mitochondrial protein). Furthermore, when repeated Ca2+ pulses (40 nmol/mg of protein each) saturated the uptake system, the mitochondria failed to release the Ca2+ accumulated. However, in each instance, the first Ca2+ pulse was accompanied by a moderate release of Ca2+, a release that was not observed during the subsequent pulses. The initial release was accompanied by a relatively marked depolarization, and by swelling, as assessed by light-scattering measurements. However, as the swelling was <50% of that observed following addition of alamethicin, it is concluded that the first Ca2+ pulse gives rise to an MPT in a subfraction of the mitochondrial population. CsA, an avid blocker of the MPT pore, only marginally increased the Ca(2+)-sequestrating capacity of the mitochondria. However, CsA eliminated the Ca2+ release accompanying the first Ca2+ pulse. The effects of CsA were shared by Ubo, but when the concentration of Ubo exceeded 20 microM, it proved toxic. The results thus suggest that brain mitochondria are different from those derived from a variety of other sources. The major difference is that a fraction of the brain mitochondria, studied presently, depolarized and showed signs of an MPT. This fraction, but not the remaining ones, contributed to the chemically and electron microscopically verified mitochondrial swelling.

Time-dependent impairment of mitochondrial function after storage and transplantation of rabbit kidneys.

BACKGROUND: The mitochondrial respiratory chain is implicated as a major target of kidney damage after ischemia-reperfusion. This study measures changes in integrated mitochondrial function and in the activity of enzymes of the respiratory chain after cold storage and transplantation-reperfusion in vivo. METHODS: Mitochondrial oxygen consumption and activities of respiratory chain enzymes and citrate synthase were measured in cortical mitochondria isolated from rabbit kidneys after 1-48 hr of cold ischemia with or without transplantation-reperfusion. RESULTS: State 4 mitochondrial oxygen consumption was significantly increased after 48 hr of ischemia or 24-48 hr of ischemia with transplantation. Prolonged (24 or 48 hr) ischemic storage with and without transplantation caused a significant decrease in state 3 oxygen consumption, as did transplantation after 1, 24, and 48 hr of cold storage. Complex I and complex II-III activity decreased after 24 or 48 hr of ischemia, with transplantation having little additional effect. Complex IV activity was significantly decreased after 48 hr of ischemia, this decrease being exacerbated by transplantation-reperfusion. Complex V activity decreased significantly after 1 hr of ischemia and continued to decrease after 24-48 hr of ischemia. Transplantation after 1-24 hr (but not 48 hr) of ischemia resulted in partial recovery of complex V activity. Citrate synthase activity was decreased significantly only after 48 hr of ischemia and reperfusion, consistent with the loss of mitochondrial membrane integrity seen in electron micrographs of the transplanted 48-hr group. CONCLUSIONS: These data suggest that individual rabbit kidney mitochondrial complexes have different susceptibilities to cold ischemic and reperfusion damage.

HSP70 induction in the brain following ethanol administration in the rat: regulation by glutathione redox state.

Changes in glutathione (GSH) and glutathione disulfide (GSSG) levels and/or redox status have been suggested to mediate the induction of heat shock proteins (HSPs) that follows exposure to oxidizing agents such as ethanol. Here we report the effects of ethanol administration to rats at intracellular levels of GSH, GSSG, HSP70, and protein carbonyls in brain and liver. Following 7 days of ethanol administration, there was a significant decrease in GSH, a significant induction of HSP70, and a significant increase in protein carbonyls in all brain regions studied and in liver. In cortex, striatum, and hippocampus there was a significant correlation between (a) the decrease in GSH, (b) the increase in GSSG, and (c) the decrease in GSH/GSSG ratio and HSP70 levels induced in response to ethanol. These data support the hypothesis that a redox mechanism may be involved in the heat-shock signal pathway responsible for HSP70 induction in the brain.

beta-Amyloid fragment 25-35 selectively decreases complex IV activity in isolated mitochondria.

Defects in mitochondrial oxidative metabolism, in particular decreased activity of cytochrome c oxidase, have been demonstrated in Alzheimer's disease, and after the expression of the amyloid precursor protein (APP) in cultured cells, suggesting that mitochondria might be involved in beta-amyloid toxicity. Recent evidence suggests that the proteolysis of APP to generate beta-amyloid is at least in part intracellular, preceding the deposition of extracellular fibrils. We have therefore investigated the effect of incubation of isolated rat brain mitochondria with the beta-amyloid fragment 25-35 (100 microM) on the activities of the mitochondrial respiratory chain complexes I, II-III, IV (cytochrome c oxidase) and citrate synthase. The peptide caused a rapid, dose-dependent decrease in the activity of complex IV, white it had no effect on the activities on any of the other enzymes tested. The reverse sequence peptide (35-25) had no effect on any of the activities measured. We conclude that inhibition of mitochondrial complex IV might be a contributing factor to the pathogenesis of Alzheimer's disease.

Effect of hydrazine upon vitamin B12-dependent methionine synthase activity and the sulphur amino acid pathway in isolated rat hepatocytes.

The effect of the industrial chemical, hydrazine (4-12 mM), on methionine synthase (EC 2.1.1.13) activity and levels of the sulphur amino acids homocysteine, cysteine, and taurine as well as GSH were investigated in vitro in isolated rat hepatocyte suspensions and monolayers in order to explain some of the adverse in vivo effects of hydrazine. None of the concentrations of hydrazine were overtly cytotoxic in hepatocyte suspensions (measured as lactate dehydrogenase [LDH] leakage) after 3 hr. However, after 24 hr in culture cells treated with 12 mM, hydrazine showed a significant increase in LDH leakage. Methionine synthase activity was reduced by hydrazine (8 and 12 mM) in suspensions (by 45 and 55%, after 3 hr) and monolayers (12 mM; 65-80% after 24 hr). This was not due to nitric oxide production and the inhibitor of nitric oxide synthase, Nomega-nitro-L-arginine, failed to protect against the hydrazine-induced loss of ATP and GSH and the reduction in urea synthesis at 24 hr. Homocysteine export was increased by 6 mM hydrazine, and total taurine content of treated cells was increased by 12 mM hydrazine. Thus, hydrazine was found to have several important and possibly deleterious effects on some parts of the sulphur amino acid pathway.

Heightened resistance of the neonatal brain to ischemia-reperfusion involves a lack of mitochondrial damage in the nerve terminal.

Mitochondria are known targets of ischemia-reperfusion injury in adult brain. Although neonates are more resistant to ischemic episodes, the mechanisms accounting for this are not yet fully understood. The aim of this study therefore was to determine whether a difference in post-ischemic mitochondrial function may play a role in the heightened recovery of the neonatal brain following ischemia-reperfusion. We have therefore compared the effects of an in vitro model of ischemia on the enzymes of the mitochondrial respiratory chain in isolated nerve terminals (synaptosomes) from neonatal and adult rats. Ischemia caused a significant, reversible decrease in mitochondrial Complex I activity in both adult and neonatal preparations. In neonatal preparations alone, ischemia also led to a significant decrease in mitochondrial Complexes II-III activity. Following 30 min of reperfusion mitochondrial Complexes II-III and IV exhibited decreased activity in synaptosomes from adult, but not neonatal rats. These data suggest a difference in the susceptibility of adult as compared to neonatal nerve terminal mitochondria to ischemia-reperfusion. These data show for the first time that nerve terminal mitochondria from immature animals remain undamaged following a period of ischemia and reperfusion, in contrast to nerve terminal mitochondria from the adult brain. This adds to the growing body of evidence that mitochondrial function plays a key role in neuronal death following cerebral ischemia reperfusion.

Effect of postischaemic hypothermia on the mitochondrial damage induced by ischaemia and reperfusion in the gerbil.

In order to test the effect of hypothermia on mitochondrial function damage following cerebral ischaemia/reperfusion, Mongolian gerbils were submitted to 30 min bilateral carotid occlusion and 2 h of reperfusion at 37 degreesC or 30 degreesC. After normothermic (37 degreesC) ischaemia/reperfusion, significant decreases in mitochondrial state 3 (+ADP) oxygen consumption (-42.2%), complex II-III activity in synaptosomes (-31.7%) and complex IV were measured, in both free mitochondria and synaptosomes (-30.3% and -27. 8% respectively). However, following hypothermic (30 degreesC) reperfusion, both respiration rates and all enzyme activities remained at levels not significantly different from those in the sham operated controls.