Although treatment of hepatitis C has improved,up to 50% do not respond to standard therapy with interferonregimes or cannot tolerate the treatment due to side effects.The purpose of the present investigation was to evaluate thesafety and effectiveness of the antiviral drug amantadine forthe treatment of hepatitis C in those who had either previouslyfailed interferon therapy or were not candidates for interferon.

A Randomized Double-blind Placebo-controlled Trial

From W.B. Cannon's identification of adrenaline with "fight or flight" to modern views of stress, negative views of peripheral physiological arousal predominate. Sympathetic nervous system (SNS) arousal is associated with anxiety, neuroticism, the Type A personality, cardiovascular disease, and immune system suppression; illness susceptibility is associated with life events requiring adjustments. "Stress control" has become almost synonymous with arousal reduction. A contrary positive view of peripheral arousal follows from studies of subjects exposed to intermittent stressors. Such exposure leads to low SNS arousal base rates, but to strong and responsive challenge- or stress-induced SNS-adrenal-medullary arousal, with resistance to brain catecholamine depletion and with suppression of pituitary adrenal-cortical responses. That pattern of arousal defines physiological toughness and, in interaction with psychological coping, corresponds with positive performance in even complex tasks, with emotional stability, and with immune system enhancement. The toughness concept suggests an opposition between effective short- and long-term coping, with implications for effective therapies and stress-inoculating life-styles.

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Arousal and physiological toughness: Implications for mental and physical health.

Studies have shown that peripheral levels of corticosterone correlate with the magnitudes of two well-described physiological models of memory, long-term potentiation (LTP) and primed burst (PB) potentiation. In the present experiments, the authors investigated the effects of experimenter-controlled manipulations of the levels of corticosterone on the magnitude of hippocampal PB potentiation in urethane-anesthetized rats. Primed burst potentiation is a long-lasting (at least 30 minutes) increase in the amplitude of the CA1 population spike and EPSP slope in response to physiologically patterned stimulation of the hippocampal commissure. The levels of serum corticosterone were controlled by implanting corticosterone pellets in adrenalectomized rats (ADX/PELLET). In the first experiment, a significant negative linear correlation between elevated (stress) levels of serum corticosterone (greater than 20 μm/dL) and the magnitude of PB potentiation in ADX/PELLET subjects (r = 0.60, P <.05) was found. In the second experiment, the shape of the corticosterone-PB potentiation function was different at low and intermediate levels of corticosterone than it was at high levels of corticosterone: There was a positive correlation at low levels (0–10 μm/dL), a peak response at intermediate levels (11–20 μm/dL), and a negative correlation at high levels (21–93 μm/dL) of corticosterone. Thus, the overall relationship between corticosterone and PB potentiation is an inverted-U function. These findings provide strong support for the hypothesis that corticosterone exerts a concentration-dependent biphasic influence on the expression of hippocampal plasticity.

Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation.

The hippocampal formation (comprising the hippocampus proper, the dentate gyrus, and the subiculum) has been repeatedly implicated in information storage models of the mammalian brain. The precise nature of the hippocampal role in the storage of information has, however, remained elusive. Here it is proposed that the role of the hippocampus is to form and retain an index of neocortical areas activated by experiential events. The hippocampal index, thus, represents those unique cortical regions activated by specific events. The neuronal mechanism underlying the memory index is hypothesized to be long-term potentiation. It is asserted that the reactivation of the stored hippocampal memory index will serve to also reactivate the associated unique array of neocortical areas and thus will result in a memorial experience. This hippocampal reactivation of a neocortical array may also be involved in establishing a cortically based memory trace.

The hippocampal memory indexing theory.

Background— Neuroprotective drugs for acute stroke have appeared to work in animals, only to fail when tested in humans. With the failure of so many clinical trials, the future of neuroprotective drug development is in jeopardy. Current hypotheses and methodologies must continue to be reevaluated, and new strategies need to be explored. Summary of Review— In part 1, we review key challenges and complexities in translational stroke research by focusing on the “disconnect” in the way that neuroprotective agents have traditionally been assessed in clinical trials compared with animal models. In preclinical studies, determination of neuroprotection has relied heavily on assessment of infarct volume measurements (instead of functional outcomes), short-term (instead of long-term) end points, transient (instead of permanent) ischemia models, short (instead of extended) time windows for drug administration, and protection of cerebral gray matter (instead of both gray and white matter). Clinical trials have often ...

Toward Wisdom From Failure: Lessons From Neuroprotective Stroke Trials and New Therapeutic Directions

Modulation of long-term potentiation by peripherally administered amphetamine and epinephrine.

Long term potentiation (LTP) has received considerable attention as a neurophysiological analog of memory. Amphetamine, as well as several other catecholamine agonists, can enhance behaviorally-assessed memory storage in a variety of training situations. The present experiments tested the effects of amphetamine on LTP produced by high frequency stimulation of the perforant path in rats. The results indicate that amphetamine can enhance the development of LTP under some but not all testing procedures. Studies of the neurobiological bases by which central and peripheral catecholamines modulate memory storage may be augmented by examinations of catecholamine effects on a specific form of long-lasting change in brain function. Similarly, the ability to manipulate LTP may prove to be an important aid in examinations of neurobiological correlates of this phenomenon.

Amphetamine effects on long term potentiation in dentate granule cells

CHAPTER 4 – ACTH Modulation of Memory Storage Processing

Post-training brain catecholamine levels: lack of response to water-motivated training.

The synthesis of catecholamines from [3H]tyrosine was studied in slices of six regions of mouse brain following footshock or ACTH injection. Immediately following a 30 minute period of footshock, there was an activation of the accumulation of [3H]DA in slices of frontal cortex. No change in the accumulation of [3H]DA was observed in slices of striatum or hypothalamus, nor of [3H]NE in slices of frontal cortex, hippocampus, hypothalamus, cerebellum, or brain stem. Thus the effect on frontal cortex DA was both regionally and catecholamine specific. Similar results were obtained with footshock treatment of adrenalectomized mice. However, dexamethasone pretreatment prevented a significant change in frontal cortex [3H]DA accumulation, but resulted in a footshock-induced increase in [3H]NE accumulation in slices of both brain stem and hypothalamus. When footshock treatment was repeated once a day for five days, and slices prepared on the sixth day, frontal cortex [3H]DA accumulation was not increased. However, the accumulation of [3H]NE in slices of hypothalamus (but not frontal cortex, hippocampus or brain stem) was increased.

Richard L. Delanoy

Papers

Modulation of long-term potentiation by peripherally administered amphetamine and epinephrine.

Amphetamine effects on long term potentiation in dentate granule cells

CHAPTER 4 – ACTH Modulation of Memory Storage Processing

Post-training brain catecholamine levels: lack of response to water-motivated training.

Hormonal involvement in footshock-induced changes in catecholamine synthesis in brain slices