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PubMed2003

Oxidative Stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis.

PURPOSE OF REVIEW: Amyotrophic lateral sclerosis, or Lou Gehrig disease, is a progressive neurodegenerative disease of adult onset characterized by a loss of motor neurons in the spinal cord and motor cortex. In the last several years, substantial progress has been made in defining the pathogenesis of motor neuron injury and relationships between disease mechanisms and the selective vulnerability of the motor neuron in both familial and sporadic forms of amyotrophic lateral sclerosis. RECENT FINDINGS: Current theories have shifted from a neuron-centered pathology to a focus on the interaction between motor neurons and glia, and their respective contributions to pathways implicated in amyotrophic lateral sclerosis. Although multiple mechanisms clearly can contribute to the pathogenesis of motor neuron injury, recent advances suggest that oxidative stress may play a significant role in the amplification, and possibly the initiation, of disease. SUMMARY: This article reviews the clinical aspects of amyotrophic lateral sclerosis and potential mechanisms of disease pathogenesis in the context of recent data supporting a major role for oxidative stress throughout the disease course. Evidence suggesting an important role for intercellular signaling is emphasized.

Amyotrophic Lateral Sclerosis↗

PubMed1995

Dissociated motor loss in forearm and hand muscles: case report.

A 27-year-old man was diagnosed with the unilateral dissociated motor loss of the forearm and hand muscles. His medical image findings were completely different from those of other reports such as so called flexion myelopathy (abnormal anterior displacement of the dura mater and the spinal cord against the posterior wall of the vertebral body in neck flexion). Our patient demonstrated lateral shift of the spinal cord to the right attributed to high thoracic scoliosis and disk herniation at the level of C6-7. The right side of the spinal cord was compressed between the disk herniation and the right lamina. In this condition, circulatory insufficiency probably occurred and resulted in damage of the anterior horn, which was selectively vulnerable for ischemia in the spinal cord.

Adult↗

PubMed1997

Neuroprotective properties of the benzodiazepine receptor, partial agonist PNU-101017 in the gerbil forebrain ischemia model.

PNU-101017 is a novel, imidazoquinoline amide and benzodiazepine receptor partial agonist that has high affinity for the GABAA receptor subtypes containing the alpha 1 and alpha 3 or alpha 5 subunits. At each of these receptors, the compound is a partial agonist with approximately 50% of the intrinsic activity of the full agonist diazepam. In view of the previously demonstrated anti-ischemic effects of some GABA agonists, the purpose of this study was to determine the ability of PNU-101017 to salvage selectively vulnerable neuronal populations in the gerbil forebrain ischemia model. In an initial set of experiments, male gerbils were pretreated 30 minutes before ischemia induction (5 minutes) with PNU-101017 (3, 10, or 30 mg/kg intraperitoneally) and again 2 hours after reperfusion. In vehicle (0.05 N HC1)-treated gerbils, the loss of hippocampal CA1 neurons at 5 days was 80%. PNU-101017 was shown to produce a dose-related increase in CA1 neuronal survival; at either 10 or 30 mg/kg, the loss of CA1 neurons was only 21% (P < 0.005 versus vehicle). A second experiment, examined the therapeutic window for PNU-101017 using the dose level of 30 mg/kg intraperitoneally. Administration of the first of two doses (2 hours apart) at the time of reperfusion resulted in an identical decrease in CA1 damage at 5 days to that seen with preischemic treatment (P < 0.003 versus vehicle). Even with a delay of the initial dosing until 4 hours after reperfusion, PNU-101017 reduced CA1 neuronal loss to only 32% (P < 0.01 versus vehicle). In a third experiment in which the duration of the ischemic insult was increased to 10 minutes and the brains were not analyzed until 28 days after ischemia, daily PNU-101017 dosing for the full 28 days still significantly preserved CA1 neurons, although less effectively than in the milder 5 minute-ischemia model. The loss of dopaminergic nigrostriatal neurons was also reduced. The neuroprotective effect of PNU-101017 was not associated with any overt CNS depression and it did not correlate with hypothermia. This benzodiazepine-receptor partial agonist may have potential for the treatment of global cerebral ischemia.

Amides↗

PubMed1998

Neuroprotective efficacy and mechanisms of novel pyrrolopyrimidine lipid peroxidation inhibitors in the gerbil forebrain ischemia model.

A brief period of bilateral carotid occlusion (BCO)-induced forebrain ischemia in gerbils triggers neuronal degeneration and the subsequent expression of amyloid precursor protein (APP), b-amyloid protein (b-AP), and apolipoprotein E (APO-E) in the selectively vulnerable CA1 region of the hippocampus. The increase in immunoreactivity is secondary to the postischemic degeneration of the CA1 neurons and is largely astrocyte-derived as evidenced by a simultaneous increase in glial fibrillary acidic protein (GFAP) staining. Oxygen radical-induced lipid peroxidation has been strongly suggested to play a role in postischemic neuronal damage and Alzheimer's disease. Recent literature suggests a possible link between early oxidative stress and APP overexpression. Therefore, the present investigation examined the effect of two novel brain-penetrating pyrrolopyrimidine lipid peroxidation inhibitors (PNU-101033E and PNU-104067F) on CA1 neurodegeneration and the subsequent increase in APP, b-AP, APO-E, and GFAP immunostaining at 4 days after a 5-minute episode of forebrain ischemia. Using an antibody for lipid peroxidation-derived malondialdehyde (MDA)-modified proteins, the authors also examined the effects of PNU-104067F on MDA immunostaining 2 days after ischemia, before completion of the neuronal loss. At 2 days, the authors also evaluated microglial activation using an antibody to surface major histocompatibility complex class II antigen expressed by activated microglia. Gerbils were treated at 30 mg/kg orally 30 minutes before the BCO and 2 hours after ischemia, followed by daily dosing for the next day (microglia and MDA) and the successive 3 days for APP, b-AP, APO-E, and GFAP immunostaining. APP and APO-E staining was significantly suppressed by 50% and 66%, respectively, with either compound. b-AP immunoreactivity was decreased 56% with both compounds, and GFAP expression was significantly decreased 53% (PNU-101033E) and 60.5% (PNU-104067F). There was a concomitant partial sparing of the CA1 hippocampal neurons by both PNU-101033E and PNU-104067F (P < .01) as determined by cresyl violet histochemistry. PNU-104067F significantly inhibited lipid peroxidation-derived MDA immunostaining and microglia activation (P < .05) at 48 hours after ischemia. Brain-penetrable lipid peroxidation inhibitors may provide attenuation of various glial response proteins after ischemic injury, probably secondary to neuronal protection.

Animals↗

PubMed1998

Neuronal stress response and neuronal cell damage after cardiocirculatory arrest in rats.

Cardiocirculatory arrest is the most common clinical cause of global cerebral ischemia. We studied neuronal cell damage and neuronal stress response after cardiocirculatory arrest and subsequent cardiopulmonary resuscitation in rats. The temporospatial cellular reactions were assessed by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining of DNA fragments, in situ hybridization (heat shock protein hsp70; immediate early genes c-fos and c-jun), and immunocytochemical (HSP70; and myeloperoxidase, specific marker of polymorphonuclear leukocytes [PMNL]) techniques. Cardiac arrest of 10 minutes' duration was induced in mechanically ventilated male Sprague-Dawley rats anesthetized with nitrous oxide and halothane. After cardiopulmonary resuscitation, animals were allowed to reperfuse spontaneously for 6 hours, 24 hours, 3 days, and 7 days (n = 6 per group). Five sham-operated animals were controls. The TUNEL staining revealed an early onset degeneration in the thalamic reticular nucleus (TRN) at 6 hours that peaked at 3 days. In contrast, degeneration was delayed in the hippocampal CA1 sector, showing an onset at 3 days and a further increase in the number of TUNEL-positive cells at 7 days. A minor portion of TUNEL-positive nuclei in the CA1 sector showed condensed chromatin and apoptotic bodies, whereas all nuclei in the TRN revealed more diffuse staining. After 6 hours of reperfusion, levels of mRNA for hsp70 and c-jun were elevated in circumscribed areas of cortex, in all hippocampal areas, and in most nuclei of thalamus, but not in the TRN. After 24 hours, a strong expression of mRNA for hsp70 and c-jun could be observed in the second layer of the cortex and in hippocampal CA1 sector; hsp70 also was observed in hippocampal CA3 sector. Some animals showed expression of hsp70 and c-jun in the dentate gyrus. After 3 days, hsp70 and c-jun were detected mainly in the CA1 sector of hippocampus. At 7 days, mRNA for both returned to control values. Therefore, delayed cell degeneration in the CA1 sector corresponds to a prolonged expression of hsp70 and c-jun in this area. In situ hybridization studies for c-fos revealed a strong signal in CA3 and dentate gyrus and a less prominent signal in TRN at 6 hours. At 24 hours, CA4 and amygdalae were positive, whereas at 3 and 7 days, the signal reached control levels; no prolonged or secondary expression was observed in the CA1 sector. Immunohistochemical study confirmed translation of HSP70 in various areas corresponding to the detection of mRNA, including the CA1 sector. The number of PMNL increased significantly at 6 hours and 7 days after cardiac arrest; PMNL were distributed disseminately and were not regionally associated with neuronal cell damage. The current data support the view that CA1 neurons might undergo an apoptosis-associated death after cardiac arrest, but PMNL are not directly involved in this process. The marked differences in the time course and the characteristics of TUNEL staining and the neuronal stress response in CA1 sector and TRN point to different mechanisms of neuronal injury in the two selectively vulnerable areas.

Animals↗

PubMed1998

Estrogen increases cGMP in selected brain regions and in cerebral microvessels.

We have previously reported that exogenous and endogenous estrogen can amplify residual cerebral blood flow during experimental cerebral ischemia. Because estrogen has been linked to nitric oxide and cyclic guanosine monophosphate (cGMP) signaling in noncerebral tissue, we tested the hypothesis that long-term 17beta-estradiol treatment increases basal cGMP in brain homogenates and cerebral microvessels in female rabbits. We also determined whether there are important baseline gender-specific differences in regional cGMP. Adult female rabbits were implanted with 17beta-estradiol pellets, 10 mg (F10, n = 10) or 50 mg (F50, n = 13), and compared with untreated females (F, n = 19) and males with negligible estrogen (M, n = 19) (plasma 17beta-estradiol levels of 4+/-4 pg/mL in M, 7+/-5 pg/mL in F, 141+/-74 pg/mL in F10, and 289 +/-10 pg/mL in F50). Cyclic GMP was determined by radioimmunoassay in cerebellum, hypothalamus, caudate nucleus, hippocampus, and cortex. Cerebral microvessels were harvested from additional cohorts of untreated males and females or estradiol-implanted females (n = 6 per group). Basal cGMP was higher in F versus M only in cerebellum. Estrogen-induced increases in regional cGMP were prominent in hippocampus at all doses (M = 43+/-26, F = 43+/-21, F10 = 84+/-24, F50 = 117+/-55 fmol/mg protein) and in cortex at the high dose (M = 78+/-55, F = 88+/-51, F10 = 69+/-34, F50 = 143+/-52 fmol/mg protein). Similarly, microvascular cGMP increased only in females treated with the 50 mg dose (M = 77+/-13, F = 86+/-25, F10O = 106+/-35, F50 = 192+/-88 fmol/mg protein). Therefore, 17beta-estradiol increases cGMP content in parenchymal regions that are known physiologic targets for reproductive steroids but are also areas of selective vulnerability to ischemic insult. Further, high doses of estrogenic steroids could amplify cGMP signaling within the cerebral microvasculature.

Animals↗

PubMed2000

Alteration of cyclic adenosine monophosphate response element binding protein in rat brain after hypoglycemic coma.

In the current study, the temporal and regional changes of the transcription factor cyclic adenosine monophosphate response element binding protein (CREB) were investigated in rat brains subjected to 30 minutes of hypoglycemic coma followed by varied periods of recovery using Western blot and confocal microscopy. The total amount of CREB was not altered in any area examined after coma. The level of the phosphorylated form of CREB decreased during coma but rebounded after recovery. In the relatively resistant areas, such as the inner layers of the neocortex and the inner and outer blades of the dentate gyms (DG), phospho-CREB increased greater than the control level after 30 minutes of recovery and continued to increase up to 3 hours of recovery. In contrast, little or no increase of phospho-CREB was observed during the recovery period in the outer layers of the neocortex and at the tip of the DG, that is, regions that are selectively vulnerable to hypoglycemic insults. The current findings suggest that a neuroprotective signaling pathway may be more activated in the resistant regions than in the vulnerable ones after hypoglycemic coma.

Animals↗

PubMed1977

Neuropathological effects of intracerebral platinum salt injections.

Multiple intracerebral injections of a mixture of platinum salts were made in 9 adult cats and the brains studied by light and electron microscopy at 5-12 days post injection. At the center of the lesions normal cortical architecture was completely replaced by edematous areas containing lipid-laden macrophages and cellular debris. The lesion periphery was characterized by perivascular edema and degenerative changes including cytoplasmic lipid inclusions and vacuolations with selective vulnerability of neurons. Membranous cytoplasmic bodies (MCB), zebra bodies and multiple nucleoli were observed in several cell types. This ultrastructural pattern, mimicked to some extent, that observed following electrical stimulation of brain following chronically implanted platinum and rhodium electrodes. The induction of zebra bodies and MCB, both of which are morphologic features of human neurolipidoses associated with congenital enzyme deficiencies, suggests an inhibitory effect of platinum on brain enzymes. Functional electrical stimulation of brain and other organs is currently being employed in a wide variety of clinical applications (14, 15). A mandatory consideration is that of the long-term effects of the stimuli as well as the electrodes themselves on the tissues involved. The histological effects and mechanisms of tissue damage following chronic application of electrical stimuli to brain have been the subject of several investigations in this laboratory (1, 14-18). Factors contributing to neural damage induced by electrical stimulation include noxious products resulting from electrode dissolution. In vitro studies employing electrochemical (3,9) and scanning electron microscopy (6) techniques have established that erosion of noble metal electrodes occurs, even when passing relatively small stimulation currents. Such electrode dissolution is of particular importance in long term applications of neural prostheses. The present study was initiated to assess the contribution of platinum electrode erosion products to neurla damage following electrical stimulation of brain, specifically to distinguish morphological changes resulting directly from electrode solubilization as opposed to electrical factors. Accordingly, intracerebral injections of graded volumes of platinum salts were made in an attempt to stimulate the presence of platinum electrode dissolution products.

Animals↗

PubMedDate not supplied

Adult-onset of Tangier disease: 1. Morphometric and pathologic studies suggesting delayed degradation of neutral lipids after fiber degeneration.

A 67-year-old woman, with the typical biochemical features of Tangier disease, had a syringomyelia-like syndrome which has now been observed in several patients with symptomatic onset in adult life. She developed progressive facial diplegia, bilateral wasting of hand muscles and loss of sensation over cranial, cervical and brachial dermatomes over 17 years. Nociception alone was first affected, then nociception and thermal discrimination and finally all modalities of sensation. Quantified tests of cutaneous sensation confirmed that sensation was normal in lower limbs but markedly abnormal in upper limbs. Biopsied fascicles of cutaneous nerves from clinically affected (forearm) and from clinically unaffected (leg) regions permitted a comparison of well-advanced and early pathologic lesions, respectively. The selective vulnerability of unmyelinated and small myelinated fibers in affected regions in this disorder has been confirmed. The earliest morphologic abnormalities of myelinated fibers, but seen infrequently, were mitochondrial enlargement and structural abnormality, aggregation of mitochondria and dense bodies and clusters of neurofilaments. Increased numbers of sudanophilic lipid droplets did not seem to form in Schwann cell cytoplasm prior to fiber degeneration. On the contrary, for myelinated fibers there appeared to be an altered process of axonal degeneration from that seen in Wallerian degeneration and in other axonal degenerations. Distinctive linear bands of closely-packed, minute, osmiophilic and clear lipid droplets formed and their further degradation appeared delayed. Although less clearly demonstrated, lipid droplets in Schwann cells of unmyelinated fibers also appeared to form following their degeneration. We would propose that in Tangier disease, the degradation of myelin ovoids to neutral lipid in Schwann cells does not appear to be delayed. However, further degradation of neutral lipid or its transport away from Schwann cells appears to be retarded.

Aged↗

PubMed1988

Brain hemosiderin and superficial siderosis of the central nervous system.

Brain tissue from five patients with superficial siderosis of the central nervous system was examined by immunocytochemistry for ferritin, glial fibrillary acidic protein (GFAP), alpha 1-antitrypsin, and alpha 1-antichymotrypsin, and by lectin affinity cytochemistry with biotinylated Ricinus communis agglutinin-1 (RCA-1). The sections were pretreated with 2,2'-dipyridyl and sodium hydrosulfite to remove iron and to reveal the antigenic sites. In siderotic cerebellar cortex, ferritin reaction product occurred in the hemosiderin matrix, the cell bodies and processes of Bergmann glia, and in microglia. Astrocytes other than Bergmann glia did not contain ferritin reaction product. RCA-1 stained microglia and hemosiderin whereas antisera to alpha 1-antitrypsin and alpha 1-antichymotrypsin only reacted with iron-depleted granules. The selective vulnerability of the eighth cranial nerve was explained by the presence of ferritin-reactive and lectin-positive microglia. Hemosiderin isolated from frozen cerebellum contained ferritin, GFAP, and vimentin. The presence of the intermediate filament proteins was likely due to co-localization with hemosiderin granules in Bergmann glia. The ability of the brain to biosynthesize ferritin in response to prolonged contact with hemoglobin iron is thought to be the most important factor in the pathogenesis of superficial siderosis. The great severity of the lesion in the exposed cerebellar cortex is readily explained by accelerated ferritin biosynthesis in Bergmann glia.

Adult↗

PubMed1993

Experimental lovastatin myopathy.

Lovastatin (LS) is a potent HMG-CoA inhibitor used in the treatment of hypercholesterolemia. In humans it can cause a severe, necrotizing myopathy with myoglobinuria and renal failure. To investigate the pathogenesis of LS-induced myopathy we studied the effects of LS on rat skeletal muscle. Lewis rats were gavage-fed 1 mg/g body weight/day of LS. Control rats received carboxymethylcellulose-based suspension by gavage. Gastrocnemius and soleus, fast and slow twitch muscles respectively, were studied by light and electron microscopy. By day 10 LS-treated rats became severely weak. Gastrocnemius was severely affected with degeneration of membranous organelles and microvacuole formation, but soleus was spared. Eventually, 20-50% of the gastrocnemius but none of the soleus fibers became necrotic. Non-necrotic fibers showed no increases of acid phosphatase, indicating that autophagy was not excited. We conclude that LS causes muscle injury by inducing degeneration of membranous organelles, and fast twitch muscle fibers are selectively vulnerable to LS myopathy.

Acid Phosphatase↗

PubMed1997

Altered calcium homeostasis and ultrastructure in motoneurons of mice caused by passively transferred anti-motoneuronal IgG.

Calcium homeostasis and ultrastructure are altered in motor axon terminals (AT) of amyotrophic lateral sclerosis (ALS) patients and in mice injected with ALS IgG and exhibit increased density of synaptic vesicles and increased intracellular calcium. To develop an immune-mediated passive transfer experimental model of both systemic weakness and altered morphology, mice were inoculated intraperitoneally with anti-motoneuronal IgG. Animals initially manifested muscle stiffness and evidence of autonomic cholinergic hyperactivity. Electron microscopic cytochemistry within 12 hours (h) demonstrated significantly increased density of synaptic vesicles and calcium both in axon terminals of neuromuscular junctions and synaptic boutons on spinal motoneurons. After 24 h the mice were severely weak and premorbid. The number of synaptic vesicles was still larger than normal, but calcium was depleted from axon terminals and synaptic boutons. The motoneuron perikarya demonstrated the dilatation of the Golgi system and the rough endoplasmic reticulum with an increased amount of calcium. The NMDA receptor antagonist, MK-801, and the L-type calcium channel antagonist, Diltiazem, prevented clinical symptoms and some morphological alterations. These data demonstrate that high titer anti-motoneuronal IgG can induce severe weakness and produce similar ultrastructural features of motor axon terminals in human ALS and in mice injected with ALS IgG, and support a key role for calcium in selective vulnerability of motoneurons.

Amyotrophic Lateral Sclerosis↗

PubMed1997

Motor and sensory specificity of host nerve axons influence nerve allograft rejection.

Previous studies have shown both survival and loss of regenerated host axons within nerve allograft segments after withdrawal of Cyclosporin A (CsA) immunosuppression. We hypothesized that the nature of end-organ reinnervation may influence the response of the axon, with survival of axons for appropriate innervation vs degeneration for inappropriate innervation. The rat femoral nerve model was chosen, as it has approximately equal sensory (S) and motor (M) divisions. Four ACI rat peroneal nerve allografts were sutured in straight (right leg: MM and SS) or switched (left leg; MS and SM) orientation in each femoral nerve transection gap in each Lewis rat recipient. Rats received CsA for 8 weeks to allow end-organ reinnervation, after which immunosuppression was discontinued. Rats were killed at various times thereafter, and underwent histologic and morphometric analysis of the graft segment axons. The regenerated axon population in the allograft reflected the nerve of origin: significantly more but smaller fibers when the proximal nerve was sensory and fewer but larger fibers when the proximal nerve was motor. After CsA withdrawal, there was a marked decrease of host axons as part of an ensuing rejection episode. The overall proportional decrease of axons was similar across all nerve orientation groups and, therefore, did not appear to be influenced by the nerve of origin or by the end-organ. However, the sensory proximal groups (SS and SM) contained more mature, noninjured fibers, while the motor proximal groups (MM and MS) contained significantly more degeneration and newly regenerating axons. We conclude that the motor or sensory nerve origin of the host axon, rather than the end-organ, influences axon survival after immunosuppression cessation. It is hypothesized that sensory axons may be more resilient while motor axons are selectively vulnerable to this second injury.

Animals↗

PubMed1997

c-Jun, JNK/SAPK kinases and transcription factor NF-kappa B are selectively activated in astrocytes, but not motor neurons, in amyotrophic lateral sclerosis.

There is increasing evidence that oxidative damage plays a major role in amyotrophic lateral sclerosis (ALS), but how it contributes to motor neuron degeneration and astrocytic gliosis, two pathologic hallmarks of the disease, is unknown. A few studies have suggested that ALS motor neurons die via apoptosis and show upregulation of c-jun, an immediate early gene that is necessary for neuronal apoptosis. In order to elucidate the mechanisms of cell damage induced by oxidant stress, we have studied in ALS and control spinal cord the immunohistochemical expression of c-Jun, of JNK/SAPK, a kinase that activates c-Jun following various types of stress, and of NF-kappa B, a transcription factor that is induced by oxidant stress and has prominent neuroprotective functions. An in situ end-labeling assay was performed for detecting apoptotic cells. We show that (a) the JNK/SAPK-c-Jun pathway is dramatically overexpressed in ALS spinal cord; (b) the strongest activation occurs in astrocytes, while motor neurons show unusually low expression of the pathway; (c) increased JNK/SAPK expression in glial cells is accompanied by NF-kappa B activation, indicating the presence of a protective response to oxidant sress, which is deficient in motor neurons; (d) activation of JNK/SAPK, c-Jun and NF-kappa B is unrelated to apoptotic cell death. These results support the view that astrocytes are directly involved in the pathologic process of ALS, and might explain the selective vulnerability of motor neurons by their relative lack of antioxidant defenses.

Amyotrophic Lateral Sclerosis↗

PubMed1998

Intracellular calcium parallels motoneuron degeneration in SOD-1 mutant mice.

Transgenic mice with Cu,Zn superoxide dismutase (SOD-1) mutations provide a unique model to examine altered Ca homeostasis in selectively vulnerable and resistant motoneurons. In degenerating spinal motoneurons of G93 A SOD-1 mice, developing vacuoles were filled with calcium, while calcium was gradually depleted from the cytoplasm and intact mitochondria. In oculomotor neurons, no degenerative changes, vacuolization, or increased calcium were noted. Motor axon terminals of interosseus muscle gradually degenerated and intracellular calcium was depleted. Oculomotor terminals of mutant SOD-1 mice were smaller and exhibited no degenerative changes, but did exhibit unique membrane-enclosed organelles containing calcium. Spinal motoneurons of SOD-1 mice were shown to have fewer calcium binding proteins, such as parvalbumin, compared with oculomotor neurons. These data suggest that the SOD-1 mutation is associated with impaired calcium homeostasis in motoneurons in vivo, with increased likelihood of degeneration associated with higher levels of intracellular calcium and lower to absent levels of calbindin-D28K and/or parvalbumin, and decreased likelihood of degeneration associated with minimally changed calcium and ample calbindin-D28K and/or parvalbumin.

Animals↗

PubMed1999

Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism.

The mechanisms for neurodegeneration in amyotrophic lateral sclerosis (ALS) are not understood. We found that motor neuron degeneration in ALS structurally resembles apoptosis. The progression of neuronal death is divisible into 3 sequential stages: chromatolysis, somatodendritic attrition, and apoptosis. In ALS spinal cord anterior horn and motor cortex, DNA fragmentation is detectable in situ and in gels and is internucleosomal, occurring in the presence of DNA fragmentation factor-45/40 activation and increased caspase-3 activity. By immunoblotting, changes occur in the subcellular distribution of cell death proteins that would promote apoptosis. In selectively vulnerable CNS regions in ALS compared with controls, the proapoptotic proteins Bax and Bak are elevated in the mitochondrial-enriched membrane compartment, but are reduced or unchanged in the cytosol. In contrast, the antiapoptotic protein Bcl-2 is decreased in the mitochondrial-enriched membrane compartment of vulnerable regions in ALS, but is increased in the cytosol, whereas Bcl-xL levels are unchanged in both subcellular compartments. Coimmunoprecipitation experiments showed that Bax-Bax interactions are greater in the mitochondrial-enriched membrane compartment of ALS motor cortex compared with controls, whereas Bax-Bcl-2 interactions are lower in the membrane compartment of ALS motor cortex compared with controls. We conclude that a PCD mechanism, involving cytosol-to-membrane and membrane-to-cytosol redistribution of cell death proteins and caspase-3 activation, participates in the pathogenesis of ALS.

Adult↗

PubMed1998

Prolonged severe hemorrhagic shock and resuscitation in rats does not cause subtle brain damage.

OBJECTIVE: Some patients who survived severe hemorrhagic shock (HS) seem to exhibit persistent subtle neurobehavioral deficits. This finding is of concern if limited hypotensive fluid resuscitation is applied in hypotensive victims with penetrating trauma. This study was designed to determine whether subtle brain damage would occur in rats after severe prolonged HS. We hypothesized that rats surviving HS with mean arterial pressure (MAP) controlled at 40 mm Hg for 60 minutes would recover with slight permanent brain damage in terms of cognitive function without morphologic loss of neurons and that rats surviving HS with MAP at 30 mm Hg for 45 minutes (60 minutes were not tolerated) would have grossly abnormal brain function and loss of neurons. METHODS: Under light nitrous oxide-halothane anesthesia, spontaneously breathing rats underwent MAP-controlled HS (HS phase I), volume resuscitation to normotension and invasive monitoring to 60 minutes (resuscitation phase II), and observation to 10 days with detailed assessment of cognitive function (observation phase III). Five conscious rats served as normal controls. Three treatment groups were compared: group 1, shams (11 of 12 rats survived to 10 days); group 2, HS at MAP 40 mm Hg for 60 minutes (10 of 17 rats survived); group 3, HS at 30 mm Hg for 45 minutes (10 of 14 rats survived). RESULTS: On post-HS day 10, all normal controls and all survivors of all three groups were functionally normal with overall performance category = 1 (normal) (overall performance category 1 = normal, 5 = death) and neurologic deficit scores < or = 7% (neurologic deficit scores 0-10% = normal, 100% = brain death). Post-HS beam balance, beam walking, and Morris water maze test results in HS groups 2 and 3 showed latencies not significantly different from those in shams and normal controls. Light microscopic scoring of five selectively vulnerable brain regions and other regions in five coronal sections revealed no ischemic (pyknotic, shrunken, eosinophilic) neurons in any of the survivors to 10 days. There was no statistical difference between normal controls, sham animals, and both HS groups in the number of normal neurons counted in the hippocampal CA-1 region in the 10-day survivors. All nonsurvivors died with intestinal necrosis. CONCLUSION: HS at MAP 40 mm Hg for 60 minutes or MAP 30 mm Hg for 45 minutes does not cause subtle functional or histologic brain damage in surviving rats. Controlling MAP at 30 mm Hg carries a risk of sudden cardiac arrest. These data suggest that limited fluid resuscitation, to maintain MAP at about 40 mm Hg, as recommended for victims of penetrating trauma with uncontrolled HS, is safe for the brain.

Animals↗

PubMedDate not supplied

Control and intrusive memories as possible determinants of chronic stress.

Amidst confusion about the nature and usefulness of the stress construct and distinctions between acute and chronic stress, research has begun to identify mechanisms by which stress affects health and by which stress can persist beyond the physical presence of the stressor. In addition, research has begun to identify reasons for selective vulnerability to chronic stress. One of the possible reasons for chronic stress following traumatic events is the disorganizing effect of loss of control and violation of expectations for regulating aspects of one's life normally under control. Data from a longitudinal study of chronic stress at Three Mile Island in the wake of the nuclear accident there suggest that loss of control and frequent experience of intrusive memories about the accident and its aftermath were related to persistent stress responding several years after the accident. The relationships between stress responding and conditioning and consolidation of stressful memories are considered as a basis for persistent intrusive memories and chronic stress.

Adaptation, Psychological↗