Mouse model of hypomyelinating disorder rescued by stem cell transplantation.
Published in the June issue of Cell Stem Cell, researchers from the University of Rochester (NY, USA) investigated the potential of glial progenitor cells to restore myelin in shiverer mice, mutant mice. These mice fail to develop myelin and usually die 18–21 days after birth. Approximately 300,000 cells were injected into each mouse shortly after birth.
Although approximately 75% of the treated mice died around the same time as untreated shiverer mice, positive effects of the treatment were found in six of the 26 mice. Of these six, two lived for longer than the untreated shiverer mice, and four were still alive after 1 year, were free from almost all symptoms and no longer suffered from seizures.
“The neurological recovery and survival of the mice receiving transplants was in sharp contrast to the fate of their untreated controls, which uniformly died by 5 months,” commented Steve Goldman, lead author of the study.
The researchers found that the stem cells had spread through the brain in all of the treated mice, despite only producing a positive effect in six of the mice. Proposing a reason why only some mice showed recovery, Goldman suggested “The animals have to live long enough for the myelinization to provide functional benefit, especially in the case of seizure incidents. They have to live long enough to get rescued.”
Despite stressing that research into this field is in a very early stage, the authors are hopeful that potential stem cell-based treatments may be developed in the future to treat myelin disorders such as leukodystrophy and multiple sclerosis.
“To our knowledge, these data represent the first outright rescue of a congenital hypomyelinating disorder by means of stem or progenitor cell transplantation,” Goldman commented. “Although much work needs to be done to maximize the number of individuals that respond to transplantation, I think that these findings hold great promise for the potential of stem cell-based treatment in a wide range of hereditary and ischemic myelin disorders in both children and adults.”
Source: Windrem MS, Schanz SJ, Guo M et al. Neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated shiverer mouse. Cell Stem Cell 2, 553–565 (2008).
Hypothermia may be more likely to harm than help in pediatric traumatic injury
Acute hypothermia therapy found to have slightly higher mortality rates than normothermia in children with traumatic brain injury.
A recent international randomized trial has cast doubt on the potential of hypothermia to reduce brain injury and mortality following traumatic brain injury in children. Published in the June issue of the New England Journal of Medicine, the study reported a higher rate of unfavorable outcomes at 6 months (severe disability, persistent vegetative state or death, measured using the Pediatric Cerebral Performance Category Scale) in hypothermia-treated children (31%) compared with normothermia controls (22%).
A total of 225 children with a mean age of 10 years who had been admitted to a pediatric intensive care unit with an acute brain injury were randomized to receive either hypothermia therapy or normothermia. Of these children, 108 received hypothermia (cooled to ∼32.5°C), initiated within 8 h of injury for 24 h. The other 117 children were randomized to normothermia, with an average temperature of 36.9oC. The 6-month mortality rate was 21% in children who received hypothermia therapy, compared with 12% in controls (p = 0.06).
After 1 year, the children treated with hypothermia also performed worse on long-term visual memory tests.
“We were very surprised by these findings, since preliminary research in adults with traumatic brain injury had demonstrated the potential benefit of hypothermia therapy,” commented Jamie Hutchison, lead author of the study. “While death rates in both groups were not statistically different, the slightly higher mortality in the hypothermia group represents a worrisome trend, which is why we advise that hypothermia therapy only be used under special circumstances.”
Source: Hutchinson JS, Ward RE, Lacroix JL et al. Hypothermia therapy after traumatic brain injury in children. N. Engl. J. Med. 358, 2447–2456 (2008).
Long-term effects of cannabis use apparent in brain structure
Structural abnormalities found in some brain regions in long-term cannabis users.
A recent study, published in the Archives of General Psychiatry, has found that long-term cannabis use is associated with decreases in brain volume in both the hippocampus and the amygdala.
Using high-resolution structural MRI, the researchers from Australia measured brain volume in 15 men (average age: 39.8 years) who had smoked at least five joints per day for more than 10 years (average duration of regular use: 19.7 years), as well as 16 individuals (average age: 36.4 years) who were not cannabis users. In addition, both the cannabis users and controls were assessed for subthreshold symptoms of psychiatric disorders and performed verbal memory tests.
The average volumes of both the hippocampus and amygdala were reduced in the long-term cannabis users compared with controls; the average hippocampal volume was 12% less and the amygdala volume 7.1% less in the cannabis users compared with controls. Long-term cannabis use was also associated with subthreshold psychotic symptoms.
The authors concluded that “These findings indicate that heavy daily cannabis use across protracted periods exerts harmful effects on brain tissue and mental health.”
Source: Yucel M, Solowij N, Respondek C et al. Regional brain abnormalities associated with long-term heavy cannabis use. Arch. Gen. Psychiatry 65(6), 694–701 (2008).
Study links air pollution to risk of stroke
US researchers find an association between fine particulate matter and ozone exposure and the risk of ischemic cerebrovascular disease.
Researchers from the University of Michigan (MI, USA) have conducted a study to investigate the association between ambient air pollution and the risk of ischemic stroke and transient ischemic attack (TIAs). The results are published in Annals of Neurology.
Lynda Lisabeth and colleagues conducted the research into the effects of air pollution in a community with a large petroleum and petrochemical industry. The Brain Attack Surveillance in Corpus Christi (BASIC) project is a population-based stroke surveillance project designed to record all the strokes occurring in Nueces County, TX, USA. The researchers obtained daily counts of ischemic strokes and TIAs from the BASIC project between 2001 and 2005. These cases were identified by trained staff, with later verification by neurologists. Daily particulate matter less than 2.5 m (PM2.5) in diameter and ozone meteorological data were also obtained for the same time period.
Lisabeth and colleagues found borderline significant associations between ischemic stroke/ TIA risk and same day and previous day exposure to fine particulate matter. They also observed similar associations between ozone exposure and stroke/TIA risk. The researchers noted that, compared with other regions in the USA, PM2.5 exposures were relatively low, possibly as a result of prevailing wind patterns and the proximity to the coast. “Although the magnitude of elevated risk of stroke/TIA due to PM2.5 exposure was relatively small, the vast majority of the public is exposed to ambient air pollution at the levels observed in this community or greater every day, suggesting a potentially large public health impact,” warn the authors.
Data suggest that particulate air pollution is associated with acute vasoconstriction of arteries and increased plasma viscosity. These changes may enhance blood clot formation, although further studies will be required to confirm this. Nevertheless, the current study supports the hypotheses that recent exposure to fine particulate matter may increase the risk of ischemic cerebrovascular events. “While our observed association between PM2.5 and stroke/TIA risk requires further study in additional regions in the US with varying types of climates and possibly with alternative study designs, it does call into question current standards for fine particulate matter and whether these standards are sufficient to protect the public with regard to stroke, our nation’s third leading cause of death,” said the authors. Furthermore, while the focus of the study was on PM2.5, the observed association between ozone levels and stroke/TIA risk suggest that ambient air pollution in general may be a risk factor.
Source: Lisabeth LD, Escobar JD, Dvonch JT et al. Ambient air pollution and risk for ischemic stroke and transient ischemic attack. Ann. Neurol. (2008) DOI: 10.1002/ana.21403 (Epub ahead of print).
Seizure drug may be used to treat alcohol dependence
While gabapentin has mainly been used in the treatment of seizures, due to its anticonvulsant properties, recent research conducted at The Scripps Research Institute suggests that the drug could be used to treat alcohol dependence.
Cellular and behavioral studies were conducted in order to analyze the effect of gabapentin on the central amygdala, a region of the brain involved in fear- and stress-related behaviors as well as regulating ethanol consumption. Previous studies have shown that gabapentin can significantly reduce alcohol intake and cravings following detoxification in alcoholics. However, the mechanism of action on gabapentin in the brain still remains to be fully elucidated. This new study provides some insight into the neural signaling mechanism of gabapentin in combating alcohol dependence.
The effects of gabapentin on the behavior of alcohol-dependent and nondependent rats were analyzed. It was found that alcohol-dependent rats that received gabapentin drank significantly less alcohol and exhibited less anxiety when faced with alcohol abstinence in comparison with rats which did not receive gabapentin. No change in behavior was seen in nondependent rats receiving the drug. Effects of gabapentin were blocked in the presence of a GABA(B) receptor antagonist, indicating that gabapentin’s cellular mechanisms are likely due to changes in the release of the transmitter GABA at inhibitory synapses.
“The results are exciting,” said Marisa Roberto (Scripps). “Our research shows that gabapentin not only changes the alcohol-consumption patterns of addicted rats (and not of the control group), but also may reverse some of the effects of addiction on a specific neurotransmitter in the brain.”
George Koob, Chair of the Scripps Research Committee on the Neurobiology of Addictive Disorders and co-Director of the Pearson Center for Alcoholism and Addiction Research added: “Cellular and behavioral studies converged to suggest that indeed gabapentin could normalize GABAergic tone in a specific brain region known to be dysregulated in dependent animals. Such results provide a strong rationale for translating these observations back to the clinical setting for the treatment of alcoholism.”
The researchers will further investigate the mechanism of action of gabapentin. Clinical trials will also be conducted to assess the efficacy of gabapentin as a treatment for alcohol dependence.
Source: Roberto M, Gilpin NW, O’Dell LE et al. Cellular and behavioral interactions of gabapentin with alcohol dependence. J. Neurosci. 28(22), 5762–5771 (2008).
Blockage of immune signaling shows hope for Alzheimer’s disease therapy
Blockade of TGF-β shown to reduce Alzheimer’s-like pathology in mice.
In an advanced online publication in Nature Medicine, researchers from the USA and Japan have demonstrated that blockade of TGF-β-Smad2/3 signaling eliminates a large proportion of amyloid-β plaques in mice genetically engineered to suffer from Alzheimer’s disease.
An interruption in the TGF-β-Smad2/3 signaling cascade resulted in an improvement in performance on maze navigation tests in the Alzheimer’s mice compared with mice in which the pathway was not interrupted. In addition, when TGF-β was blocked, the immune system of the mice released peripheral macrophages which crossed the BBB and surrounded the β-amyloid plaques and cerebral vessels. Impressively, up to 90% of amyloid plaques were eliminated from the brains of the Alzheimer’s disease mice following the TGF-β block.
The authors are hopeful that blockade of TGF-β-Smad2/3 signaling in peripheral macrophages may be a novel target for Alzheimer’s therapy. “If results from our study in mice engineered to develop Alzheimer's-like dementia are supported by studies in humans, we may be able to develop a drug that could be introduced into the bloodstream to cause peripheral immune cells to target the amyloid plaques,” explained Terrence Town, lead author of the study.
Source: Town T, Laouar Y, Pittenger C et al. Blocking TGF–Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat. Med. (2008) (Epub ahead of print).