Many mild preconditioning stress conditions, including physical and metabolic injuries, increase the resistance of neurons to subsequent more severe stresses of the same or different type. This “tolerance phenomenon” lasts one to several weeks, providing a unique opportunity to investigate endogenous neuroprotective mechanisms. The aim of this study was to find a physiological and easily applicable preconditioning stimulus able to confer protection against convulsant-induced neuronal damage and seizures. We found that moderate transient hyperthermic preconditioning markedly reduced kainic-acid-induced neuronal cell loss and attenuated susceptibility to bicuculline-induced seizures. Prevention of cell damage (approximately 50%) was efficient both in vitro in organotypic hippocampal slice cultures and in vivo in adult rats. This protection lasted about 1 week and peaked 3 to 5 days after pretreatment. Unraveling the mechanisms of heat shock preconditioning-induced protection against epilepsy should lead to the development of new therapeutic strategies. (via.)
Duman’s team did whole genome scans on tissue samples from 21 deceased individuals who had been diagnosed with depression and compared gene expression levels to those of 18 individuals who had not been diagnosed with depression. They found that one gene called MKP-1 was increased more than two-fold in the brain tissues of depressed individuals.
This was particularly exciting, say the researchers, because the gene inactivates a molecular pathway crucial to the survival and function of neurons and its impairment has been implicated in depression as well as other disorders. Duman’s team also found that when the MKP-1 gene is knocked out in mice, the mice become resilient to stress. When the gene is activated, mice exhibit symptoms that mimic depression.
The finding that a negative regulator of a key neuronal signaling pathway is increased in depression also identifies MKP-1 as a potential target for a novel class of therapeutic agents, particularly for treatment resistant depression. (via.)
Interesting tidbits from elsewhere:
- Interestingly enough the bodies endogenous cannabanoid anandamide actually increases the expression of MKP-1 in microglial cells to protection from inflammation in the brain.
- MKP-1 controls axon branching and is induced by BDNF signaling.
- Brain damage and cardiac arrest: hypothermia, which induces the expression of MKP-1, protects against TNF-alpha-induced endothelial barrier dysfunction and apoptosis through an MKP-1-dependent mechanism.
- “MAP kinase phosphatase-1 (MKP-1), is an important modulator of cellular inflammatory responses, and we recently reported that heat shock increases expression of MKP-1. [...] mRNA stability assays demonstrated that heat shock increased MKP-1 mRNA stability compared with cells maintained at 37 degrees C. [...] These data demonstrate that heat shock regulates MKP-1 gene expression at both the transcriptional and posttranscriptional levels.”
- “Application of heat shock before an inflammatory stimulus often results in an attenuated response to that stimulus. As a result, it has become increasingly appreciated that heat shock may induce cross-tolerance to a variety of stimuli based on in vitro and in vivo models. [...] The effect of heat shock on decreasing the tumor necrosis factor response to lipopolysaccharide is conferred by induction of MKP-1, which negatively regulates p38 and ERK kinases.”
- Heat shock activates MKP-1 expression in leydig testicular cells.