Hibernation-Suppression and Trauma-Induction of Inflammation
Inflammation/hibernation is a complex story at the foundation of chronic diseases. Inflammation is the common thread -- activation of the inflammation transcription factor NFkB.
Trauma Causes Life-Threatening TraumaTrauma, everything from a bee sting to a horrific traffic accident that causes head and spine injuries, results in initial tissue damage and subsequent inflammation damage. The inflammatory response to punctures and abrasions is usually appropriate and self-limiting. The immune response to serious injuries is frequently more life-threatening than the initial damage.
Transplanted Organs Suffer from InflammationOrgans removed for transplantation are subjected to a certain amount of necessary trauma and oxygen deprivation. If the organ was simply popped into a waiting recipient biochemically unaware of the process, the initial damage would be readily repaired in its new home. Unfortunately, some of the organs overreact and become damaged by their own immune/inflammatory reaction to the surgery.
Hibernation Reduces Trauma InflammationOrgan transplants between animals that are hibernating, are much more successful, because the damaging inflammation is suppressed. Hibernation in animals or in human organs can be induced by the use of opioid peptides, e.g. DADLE, and subsequent surgical procedures are more successful. Hibernation also provides protection against experimental stroke. Apparently, the activation of the opioid receptor suppresses activation of NFkB and avoids inflammation.
Opioids and Steroid Hormones Block NFkB Activation and InflammationSteroid hormones can also provide protection against inflammatory damage resulting from head trauma. Thus, the ubiquitous steroid receptors may also block NFkB activation and inflammation.
Trauma Releases ATP that Triggers P2X7 and NFkBExtracellular ATP can activate NFkB activity and inflammation, and ATP accumulation at trauma sites may be particularly dangerous for spinal injuries. Inhibitors of ATP binding to the purinic receptor P2X7, block inflammation and provide dramatic improvement in the return of function in animal models of spinal injuries. Most of the common inhibitors of P2X7 signaling must be injected directly into the traumatized tissue to block inflammation, because they can’t cross the blood-brain barrier. An exception is Brilliant Blue G.
Brilliant Blue G Blocks Trauma InflammationBrilliant Blue G, a.k.a. Coomasie Brilliant Blue,
should be very well known to molecular biologists, because it is the com
monly used stain for proteins separated on SDS-PAGE gels. I used that dye literally thousands of times to stain gels and I even tried it to stain the extracellular matrix surround cartilage-secreting cells, chondrocytes, grown in culture. I have included one of those pictures just for old times sake.
BBG can be injected IV i
nto mice and the result is amazing. Not only do the mice become blue, but they recover much better from experimental spinal trauma. BBG in the blue mice blocks inflammation due to the surge in tissue ATP and the mice heal their trauma and regain function.
It would be amazing if BBG worked on people with spinal injuries. I expect the rapid development of a suitable drug to help spine and head trauma patients.
Can Manipulation of Hibernation Cure Chronic Diseases?A big question
is whether or not similar drugs might be used to block inflammation that supports cancer and other forms of chronic illness. Alternatively, in some instances the problem is that bacteria are suppressing local inflammation and inducing tissue hibernation to produce chronic illness. Under these circumstances, the induction of local inflammation or elimination of hibernation may make the bacteria vulnerable to attack.
references:
Borlongan CV, Hayashi T, Oeltgen PR, Su TP, Wang Y. Hibernation-like state induced by an opioid peptide protects against experimental stroke. BMC Biol. 2009 Jun 17;7:31.
W. Penga, M. L. Cotrinaa, X Hana, H Yua, L. Bekara, L. Bluma, T. Takanoa, G.-F. Tiana, S. A. Goldman and M. Nedergaard. 2009. Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. PNAS 106:12489