Endogenous Protective Factors Research Articles

Endocannabinoids mediate neuroprotection after transient focal cerebral ischemia

The endocannabinoids anandamide (AEA) and palmitoylethanolamide (PEA) act as endogenous protective factors of the brain, using different pathways of neuroprotection against neuronal damage. Although several in vivo and in vitro studies confirmed the neuroprotective efficacy of endocannabinoids, no experimental settings compare and explore the neuroprotective potential of AEA and PEA in an acute stroke model. In this study, we investigated the neuroprotective potential by infarct measurement after high (30 mg/kg body weight) and low dosage administration (10 mg/kg body weight) of the endocannabinoid PEA in 49 male Wistar rats. In additions we studied infarct volumes of 22 male Wistar rats receiving the endocannabinoid AEA with a dosage of 10 mg/kg body weight or placebo. The neurological outcome was assessed 24 h after ischemia. Endocannabinoids were given intraperitoneally 30 min after initiation of transient middle cerebral artery occlusion (tMCAO). Infarct volume was calculated on the basis of 2.3.5-triphenyltetrazolium chloride staining. In the PEA high-dose group a significant total infarct reduction of 35% compared to the control group could be observed. AEA-treated rats presented a total infarct reducing effect of 26% compared to controls. Neurological scores, evaluated 24 h after tMCAO and physiological parameters, obtained 45 and 90 min after onset of ischemia showed no significant differences among the groups. As shown here, the endocannabinoids AEA and PEA achieved a significant neuroprotective effect by reducing size of infarcted tissue after tMCAO. Both endocannabinoids may have the potential to treat acute stroke and exert neuroprotection through a variety of mechanisms.

New insights into the anti-inflammatory actions of aspirin- induction of nitric oxide through the generation of epi-lipoxins

Aspirin has always remained an enigmatic drug. Not only does it present with new benefits for treating an ever-expanding list of apparently unrelated diseases at an astounding rate but also because aspirin enhances our understanding of the nature of these diseases process. Originally, the beneficial effects of aspirin were shown to stem from its inhibition of cyclooxygenase-derived prostaglandins, fatty acid metabolites that modulate host defense. However, in addition to inhibiting cyclooxygenase activity aspirin can also inhibit pro-inflammatory signaling pathways, gene expression and other factors distinct from eicosanoid biosynthesis that drive inflammation as well as enhance the synthesis of endogenous protective anti-inflammatory factors. Its true mechanism of action in anti-inflammation remains unclear. Here the data from a series of recent experiments proposing that one of aspirin's predominant roles in inflammation is the induction of nitric oxide, which potently inhibits leukocyte/endothelium interaction during acute inflammation, will be discussed. It will be argued that this nitric oxide-inducing effects are exclusive to aspirin due to its unique ability, among the family of traditional anti-inflammatory drugs, to acetylate the active site of inducible cyclooxygenase and generate a family of lipid mediators called the epi-lipoxins that are increasingly being shown to have profound roles in a range of host defense responses.

Regulation of neuronal death by endogenous protective factors

Glutamate is postulated to play an important role in the pathogenesis of the neuronal cell loss that is associated with neurological disorders in the CNS. Nitric oxide (NO) mediates glutamate neurotoxicity observed in the primary culture derived from the cerebral cortex, substantia nigra and retina. In search of endogenous protective factors that inhibit the neurotoxic action of glutamate and NO, we found that certain neurotransmitters such as nicotinic acetylcholine, dopamine and cholecystokinin prevent glutamate neurotoxicity by suppressing the activity of NO synthase. Neurotrophins such as brain-derived neurotrophic factor (BDNF) also prevented glutamate neurotoxicity via TrkB neurotrophin receptors although prolonged pretreatment was necessary to induce marked neuroprotection. BDNF prevented the neurotoxic actions of NO donors. This evidence indicates that BDNF protects neurons against glutamate cytotoxicity by reducing the radical chain reaction triggered by NO. We also found that the conditioned medium of the striatal cultures reduced glutamate neurotoxicity. Moreover, ether extract of fetal calf serum (FCS), contained in the conditioned medium, also reduced glutamate neurotoxicity. Concomitant application of ether extract of FCS with S-nitrosocysteine (SNOC), a NO donor, markedly reduced SNOC-induced neurotoxicity. These substances may have roles as neuroprotective factors that promote neuron survival under neurological disease states in the CNS.

Therapeutic approaches for the prevention of secondary brain injury.

The precise mechanisms underlying secondary brain damage after traumatic injury to the central nervous system (CNS) are not well understood, and delayed neuronal injury may result from pathological changes in neurotransmitter release, synthesis or generation of endogenous autodestructive neurochemicals and/ or inflammatory mediators, or alterations in endogenous protective or trophic factors. Recent identification of such factors and the elucidation of the timing of the neurochemical cascade following CNS injury provides a window of opportunity for therapeutic intervention with pharmacological compounds which modify synthesis, release, receptor binding or physiological activity of neurotoxic factors. A number of recent experimental studies have reported that pharmacological modification of the post-traumatic neurochemical milieu can promote functional recovery in a variety of animal models of CNS trauma. This paper summarizes recent work suggesting that pharmacological manipulation of several key neurotransmitter and neurochemical systems can attenuate neuronal damage and improve functional outcome associated with traumatic brain injury.

Therapeutic approaches for the prevention of secondary brain injury

The precise mechanisms underlying secondary brain damage after traumatic injury to the central nervous system (CNS) are not well understood, and delayed neuronal injury may result from pathological changes in neurotransmitter release, synthesis or generation of endogenous autodestructive neurochemicals and/or inflammatory mediators, or alterations in endogenous protective or trophic factors. Recent identification of such factors and the elucidation of the timing of the neurochemical cascade following CNS injury provides a window of opportunity for therapeutic intervention with pharmacological compounds which modify synthesis, release, receptor binding or physiological activity of neurotoxic factors. A number of recent experimental studies have reported that pharmacological modification of the post-traumatic neurochemical milieu can promote functional recovery in a variety of animal models of CNS trauma. This paper summarizes recent work suggesting that pharmacological manipulation of several key neurotransmitter and neurochemical systems can attenuate neuronal damage and improve functional outcome associated with traumatic brain injury.