Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is now well established that neurons and other cell types may die many hours or even days after hypoxic-ischemic injury due to activation of programmed cell death (apoptotic) pathways. The potent anti-apoptotic factor IGF-1 and its binding proteins and receptors are intensely induced within damaged brain regions following brain injury suggesting a possible a role for IGF-1 in endogenous brain recovery. Exogenous administration of IGF-1 within a few hours after brain injury has now been shown to be protective in both grey and white matter, and leads to improved long-term neurological function. The limited window of opportunity for treatment with IGF-1 can be extended by spontaneous mild post-hypoxic hypothermia, probably due to delayed evolution of apoptotic processes. The efficacy of IGF-1 is specific to particular cellular phenotypes and brain regions, and its neuroprotective effects are mediated by IGF-1 receptors and binding proteins. Intriguingly its naturally cleaved N-terminal tripeptide (glycine-proline-glutamate, GPE) has been demonstrated to be neuroprotective after both central and peripheral administration. Peripheral administration of GPE also prevents the loss of dopamine neurons and improves long-term functional recovery following 6-OHDA lesion. However, GPE is unlikely to contribute significantly to the direct effects of IGF-1.
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PMID:Treatment in animal models. 1587 86

Brain ischemia induces the IGF-1 system in damaged regions, and exogenous administration of IGF-1 after injury is neuroprotective and improves long-term neurological function. The short treatment window can be extended by mild hypothermia, probably due to delayed apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential preclude clinical application. The N-terminal tripeptide of IGF-1 (glycine-proline-glutamate, GPE) is neuroprotective after central administration. Central uptake of GPE is injury dependent, and it is rapidly degraded in the plasma. Intravenous infusion of GPE prevents brain injury and improves long-term functional recovery, with a broad effective dose range and a 3-7 hour therapeutic window. GPE does not interact with IGF receptors. G-2meth-PE, a GPE analogue with improved stability, has a prolonged plasma half life and is neuroprotective after ischemic injury. Neuroprotection by GPE and its analogue may involve modulating inflammation, promoting astrocytosis and inhibiting apoptosis, and the analogue may have a vascular effect. Cyclo-glycyl-proline (cGP) is an endogenous diketopiperazine possibly derived from GPE. Cyclic GP and its analogue cyclo-L-glycyl-L-2-allylproline (cG-2allylP) are neuroprotective after ischemic injury. cG-2allylP crosses the BBB independent of injury and remains detectable several hours after a single administration. Repeated peripheral administration of cG-2allyP improves somatosensory-motor function and long-term histological outcome.
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PMID:Insulin-like growth factor-1 and its derivatives: potential pharmaceutical application for ischemic brain injury. 1853 71

Ischemic brain damage remains a major cause of disability at all ages. This review examines the efficacy, mode of action and mechanisms of insulin-like growth factor (IGF)-1 and its derivatives in animal models of acute brain injury and neurodegenerative conditions, their potential in pharmaceutical developments. IGF-1 reduces cell loss and improves long-term neurological function in animal models. IGF-1 needs to be given within a few hours of the insult. However, the therapeutic window can be extended by mild hypothermia, likely by delaying apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential limit clinical translation. Thus, recent studies have examined related compounds. For example, intravenous infusion of the N-terminal tripeptide of IGF-1 (glycine- proline-glutamate, GPE) can alleviate brain injury and improve long-term function in rats, with a broad effective dose range and a 3-7 hour therapeutic window, but has a short half-life. G-2meth-PE(G-2mPE), a GPE analogue with a longer half-life, is also neuroprotective. GPE/G-2mPE do not interact with IGF receptors and may act by modulating postinjury inflammation, astrogliosis and vascular remodeling. Cyclo-glycyl-proline (cGP), an endogenous diketopiperazine possibly derived from GPE is also neuroprotective. An analogue, cyclo-L-glycyl-L-2-allylproline (NNZ-2591) improves long-term somatosensory-motor function and histology after ischemic injury. Treatment with NNZ-2591 after 6-hypdroxydopamine injection in adult rats improves neurogenesis and long-term motor function. Further, oral administration of NNZ-2591 also prevents scopolamine-induced acute memory impairment. These beneficial effects may mediated by improved neuroplasticity. This review is an updated version of a previous publication in Recent Pat CNS Drug Discov.
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PMID:Insulin-like growth factor-1 and its derivatives: potential pharmaceutical application for treating neurological conditions. 2359 5