Study reveals how anesthetic isoflurane induces Alzheimer's-like changes in mammalian brains

The association of the inhaled anesthetic isoflurane with Alzheimer's-disease-like changes in mammalian brains may by caused by the drug's effects on mitochondria, the structures in which most cellular energy is produced. In a study that will appear inAnnals of Neurology and has received early online release, Massachusetts General Hospital (MGH) researchers report that administration of isoflurane impaired the performance of mice on a standard test of learning and memory – a result not seen when another anesthetic, desflurane, was administered. They also found evidence that the two drugs have significantly different effects on mitochondrial function.

"These are the first results indicating that isoflurane, but not desflurane, may induce neuronal cell death and impair learning and memory by damaging mitochondria," says Yiying (Laura) Zhang, MD, a research fellow in the MGH Department of Anesthesia, Critical Care and Pain Medicine and the study's lead author. "This work needs to be confirmed in human studies, but it's looking like desflurane may be a better anesthetic to use for patients susceptible to cognitive dysfunction, such as Alzheimer's patients."

Previous studies have suggested that undergoing surgery and general anesthesia may increase the risk of Alzheimer's, and it is well known that a small but significant number of surgical patients experience a transient form of cognitive dysfunction in the postoperative period. In 2008, members of the same MGH research team showed that isoflurane induced Alzheimer's-like changes – increasing activation of enzymes involved with cell death and generation of the A-beta plaques characteristic of the disease – in the brains of mice. The current study was designed to explore the underlying mechanism and behavioral consequences of isoflurane-induced brain cell death and to compare isoflurane's effects with those of desflurane, another common anesthetic that has not been associated with neuronal damage.

In a series of experiments, the investigators found that the application of isoflurane to cultured cells and mouse neurons increased the permeability of mitochondrial membranes; interfered with the balance of ions on either side of the mitochondrial membrane; reduced levels of ATP, the enzyme produced by mitochondria that powers most cellular processes; and increased levels of the cell-death enzyme caspase. The results also suggested that the first step toward isoflurane-induced cell death was increased generation of reactive oxygen species – unstable oxygen-containing molecules that can damage cellular components. The performance of mice on a standard behavioral test of learning and memory declined significantly two to seven days after administration of isoflurane, compared with the results of a control group. None of the cellular or behavioral effects of isoflurane were seen when the administered agent was desflurane.

In another study by members of the same research team – appearing in the February issue of Anesthesia and Analgesia and published online in November – about a quarter of surgical patients receiving isoflurane showed some level of cognitive dysfunction a week after surgery, while patients receiving desflurane or spinal anesthesia had no decline in cognitive performance. That study, conducted in collaboration with investigators from Beijing Friendship Hospital in China, enrolled only 45 patients – 15 in each treatment group – so its results need to be confirmed in significantly larger groups.

"Approximately 8.5 million Alzheimer's disease patients worldwide will need anesthesia and surgical care every year," notes Zhongcong Xie, MD, PhD, corresponding author of both studies and director of the Geriatric Anesthesia Research Unit in the MGH Department of Anesthesia, Critical Care and Pain Medicine. "Developing guidelines for safer anesthesia care for these patients will require collaboration between specialists in anesthesia, neurology, geriatric medicine and other specialties. As the first step, we need to identify anesthetics that are less likely to contribute to Alzheimer's disease neuropathogenesis and cognitive dysfunction." Xie is an associate professor of Anesthesia at Harvard Medical School (HMS)

Provided by Massachusetts General Hospital

"Study reveals how anesthetic isoflurane induces Alzheimer's-like changes in mammalian brains." March 1st, 2012.http://medicalxpress.com/news/2012-03-reveals-anesthetic-isoflurane-alzheimer-like-mammalian.html

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Robert Karl Stonjek

How marijuana impairs memory

A major downside of the medical use of marijuana is the drug's ill effects on working memory, the ability to transiently hold and process information for reasoning, comprehension and learning. Researchers reporting in the March 2 print issue of the Cell Press journal Cell provide new insight into the source of those memory lapses. The answer comes as quite a surprise: Marijuana's major psychoactive ingredient (THC) impairs memory independently of its direct effects on neurons. The side effects stem instead from the drug's action on astroglia, passive support cells long believed to play second fiddle to active neurons.

The findings offer important new insight into the brain and raise the possibility that marijuana's benefits for the treatment of pain, seizures and other ailments might some day be attained without hurting memory, the researchers say.

With these experiments in mice, "we have found that the starting point for this phenomenon – the effect of marijuana on working memory – is the astroglial cells," said Giovanni Marsicano of INSERM in France.

"This is the first direct evidence that astrocytes modulate working memory," added Xia Zhang of the University of Ottawa in Canada.

The new findings aren't the first to suggest astroglia had been given short shrift. Astroglial cells (also known as astrocytes) have been viewed as cells that support, protect and feed neurons for the last 100 to 150 years, Marsicano explained. Over the last decade, evidence has accumulated that these cells play a more active role in forging the connections from one neuron to another.

The researchers didn't set out to discover how marijuana causes its cognitive side effects. Rather, they wanted to learn why receptors that respond to both THC and signals naturally produced in the brain are found on astroglial cells. These cannabinoid type-1 (CB1R) receptors are very abundant in the brain, primarily on neurons of various types.

Zhang and Marsicano now show that mice lacking CB1Rs only on astroglial cells of the brain are protected from the impairments to spatial working memory that usually follow a dose of THC. In contrast, animals lacking CB1Rs in neurons still suffer the usual lapses. Given that different cell types express different variants of CB1Rs, there might be a way to therapeutically activate the receptors on neurons while leaving the astroglial cells out, Marsicano said.

"The study shows that one of the most common effects of cannabinoid intoxication is due to activation of astroglial CB1Rs," the researchers wrote.

The findings further suggest that astrocytes might be playing unexpected roles in other forms of memory in addition to spatial working memory, Zhang said.

The researchers hope to explore the activities of endogenous endocannabinoids, which naturally trigger CB1Rs, on astroglial and other cells. The endocannabinoid system is involved in appetite, pain, mood, memory and many other functions. "Just about any physiological function you can think of in the body, it's likely at some point endocannabinoids are involved," Marsicano said.

And that means an understanding of how those natural signaling molecules act on astroglial and other cells could have a real impact. For instance, Zhang said, "we may find a way to deal with working memory problems in Alzheimer's."

More information: Han et al.: "Acute Cannabinoids Impair Working Memory through Astroglial CB1 Receptor Modulation of Hippocampal LTD."

Provided by Cell Press

"How marijuana impairs memory." March 1st, 2012. http://medicalxpress.com/news/2012-03-marijuana-impairs-memory.html

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Robert Karl Stonjek

Online treatment reaps rewards for teenagers with chronic fatigue

Teenagers who were able to consult therapists by email reported a drastic reduction in symptoms of chronic fatigue syndrome. Credit: Flickr/Ev0luti0nary

A web-based therapeutic program for adolescents with chronic fatigue syndrome is at least three times more effective in reducing symptoms of the disorder than regular treatment, one study has found.

Researchers who studied the impact of the Fatigue In Teenagers on the interNET (FITNET) program on a group of adolescents found that the web-based treatment dramatically reduced fatigue, school absence, and physical dysfunction in just six months.

Under the FITNET program, patients can log in and send e-mails to trained cognitive behavioural psychotherapists at any time. Therapists respond to the e-consultations on set days, but also reply immediately to emergency emails.

The patients are expected to keep diaries, answer questionnaires, and take part in reviews of each step in their treatment.

For the study, researchers from The Netherlands recruited 135 adolescents who had suffered from chronic fatigue syndrome for almost 2 years; 68 were randomly assigned to FITNET and 67 to usual care, which consisted mainly of individual and group cognitive behavioral therapy or graded exercise therapy.

After six months, 85% of adolescents in FITNET group reported that they no longer suffered from severe fatigue, compared with 27% in the second group; 78% reported normal physical functioning, compared with 20%; while full school attendance was attained by 75% of students, compared with just 16%.

The results of the study are published online today in the journal The Lancet.

It is estimated that between 40,000 and 140,000 Australians suffer from chronic fatigue syndrome, a mysterious illness of unknown cause that may be linked to a virus. Patients complain they are routinely humiliated and ostracized by people who do not take their physical suffering seriously, because they regard the condition as a psychological, rather than a biological, one.

Sanne Nijhof from the University Medical Centre Utrecht in The Netherlands, and lead author of the research, said that with e-consultations, “effective treatment is within reach for any adolescent with [chronic fatigue syndrome]. These findings stress the need for proper and rapid diagnosis and making medical professionals aware of adolescent chronic fatigue and the treatment options.”

“Web-based treatment has general advantages: it is available at any time, avoids face-to-face treatment barriers – [such as] treatment delay due to poor accessibility, inconvenience of scheduling appointments, missing school or work, travelling to or from a clinician’s office – and reduces treatment time and costs.”

The report concluded that it was unclear which aspect of the FITNET program – “such as being readily accessible soon after diagnosis, 24-hour availability, anonymity, or professional feedback by a trained psychotherapist, is the reason for this increased effectiveness.”

Rosanne Coutts, an Accredited Exercise Physiologist and Lecturer in Sport and Exercise Psychology at Southern Cross University, said the results demonstrated the importance of the psychological aspects within treatment processes.

“By using the internet, which adolescents are very familiar with, they have met them "where they live”,“ Dr. Coutts said. "The patients also seemed fairly involved in what they did, it was quite self-driven, putting patients back in charge of their own recovery. Further detail about the actual physical activity conducted in both groups would be of interest and would assist with understanding any physiological changes that had also occurred.

“The study also relied on self-report, however even with consideration for some self-reporting bias the school attendance is a clear indicator of levels of recovery. Previous studies report a good prognosis for adolescents and this study again supports this.”

Professor Anthony Cleare, a consultant psychiatrist at the Institute of Psychiatry, Kings College London, said that although the effectiveness of cognitive behavioral therapy for chronic fatigue syndrome was beyond doubt, the lack of suitably trained therapists could limit benefits for patients.

“That an internet based therapy is so effective is very good news for patients who either cannot access a therapist, or who prefer therapy delivered over the internet,“ Professor Cleare said. "Indeed, the internet may be a particularly attractive medium for adolescents who have grown up accustomed to using it regularly.

“No one would suggest that the internet can replace face-to-face therapy, but this study suggests that it can certainly be a highly effective alternative in some patients."

Provided by The Conversation

This story is published courtesy of the The Conversation (under Creative Commons-Attribution/No derivatives).

"Online treatment reaps rewards for teenagers with chronic fatigue." March 1st, 2012. http://medicalxpress.com/news/2012-03-online-treatment-reaps-rewards-teenagers.html

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Robert Karl Stonjek