Neuroprotective properties

It has been revealed that cannabinoids exhibit neuroprotectant activities in both in vitro and in vivo models [249]. The neuroprotective effects are mainly based on regulation of transmitter release, modulation of calcium homeostasis, anti-oxidant properties and modulation of immune responses. A number of neurological disorders, including brain trauma, cerebral ischaemia, Parkinson s disease and Alzheimer s disease represent possible therapeutic areas for cannabinoids with neuroprotective properties. Cannabinoids are also suggested to have potential against glaucoma due to their neuroprotective nature and lowering of intraocular pressure [250]. 

The newly isolated dihydroxy-containing DHA derivative is called neuroprotectin Dl (NPD1) (1) because of its neuroprotective properties in brain ischemia-reperfusion [16] and in oxidative-stress-challenged retinal pigment epithelial cells [17] (2) because of its potent ability to inactivate proapoptotic signaling (Bad and Bid) and to upregulate Bcl-2 and Bcl-xl and (3) because it is the first identified neuroprotective mediator of DHA. 

Studies evaluating its neuroprotective properties suggest that selegiline can delay the need for L-dopa by about 9 months and has symptomatic effects, but there is no firm evidence that it can slow neurodegeneration. 

Zangara A. (2003) The psychopharmacology of huperzine A An alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer s disease. Pharmacol BiochemBehav 75 675-686. 

Flavonoids in the diet have been widely promoted as important antioxidant contributors. Their neuroprotective properties, because of this effect, have been demonstrated by several workers. However, they have also been demonstrated to have MAOI activity and this has been proposed as part of the explanation of the use of the common herb, St Johns Wort, Hypericum perforatum L., as an antidepressant. This dual role has now been proposed for a variety of flavonoids, such as kaempferol (22) from the leaves of Ginkgo biloba L., a widely used herbal product which has been suggested as a preventative agent against neurodegeneration. Quercetin (23), similarly, has also shown to inhibit MAO-B " and reverse the effects of induced catalepsy, which mimics the bradykinesia associated with PD. Tangeretin (24) also inhibits MAO-B and crosses the blood brain barrier in a rat model. 

L., Zhong, W., Xiao, J., Hu, Y., Li, S. (2006) FK506-binding protein ligands structure-based design, synthesis, and neurotrophic/neuroprotective properties of substituted 5,5-dimethyl-2-(4-thiazolidine)carboxylates. / Med Chem 49, 4059 071. 

Akaike et al. have examined the neuroprotective properties of serofendic acid, a substance isolated from serum. The compound was found to protect neuronal cells from both glutamate and NO. This was attributed to the scavenging of OH radicals (from the decomposition of ONOO-) rather than NO itself.320 Indeed, Ueda and colleagues have demonstrated the formation of both NO and OH in neuronal cells upon stimulation of the NMDA receptor.321 These workers also trapped lipid radicals in the brains of rats undergoing seizures induced by the stimulation of a subset of glutamate receptors with kainic acid. Polyphenols have been shown to exacerbate the neurotoxicity of NO.322... 

Taken together, these results showed that EGb can prevent ischemia-induced Na,K-AIPase injury, and suppress hypoxia- and ECS-induced membrane phospholipid breakdown in the brain, and bilobalide might be associated with its protective action. In addition, EGb reduces AA-induced neuronal damage as a consequence of the increase in reincorporation of AA Therefore, these mechanisms might provide a possible explanation for neuroprotective properties of EGb and bilobalide against oxidative damage. 

With respect to recent patent applications the neuroprotective properties of non-NMDA antagonists are still in the focus of pharmacetical research, but the majority of patents does not propose that they should be used for pain relief. However, the continuing interest in AMPA/kainate receptor modulators might also lead to further investigations of their analgesic properties. Two examples of AMPA receptor modulators recently claimed for pain are shown. 

Weiser, T., Brenner, M., Palluk, R., Bechtel, W.D., Ceci, A., Brambilla, A., Ensinger, H.A., Sagrada, A., Wienrich, M. BIIR 561 CL A novel combined antagonist of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and voltage-dependent sodium channels with anticonvulsive and neuroprotective properties, J. Pharmacol. Exp. Ther. 1999, 289, 1343-1349. 

EGb 761 might also directly scavenge peroxynitrites and inhibit lipid peroxidation because it has been reported both to block the cytotoxicity induced by peroxynitrites and inhibit cyclosporine-A-induced peroxidation. This hypothesis is supported by the finding that the purported anti-ischemic agent ebselen completely protected and rescued hippocampal cells against SNP-induced toxicity. In contrast, the hydroxyl radical scavenging properties of EGb 761 do not seem able to account for its protective effects because catalase failed to display any neuroprotective properties in this model. 

Treatment with the PI3-K inhibitor wortmannin reduces the number of surviving RGCs after retinal ischemia/reperfusion suggesting that, Akt activation is indeed endowed with RGCs neuroprotective properties and represents a prosurvival response of the retina to the ischemic injury (Russo et al., 2008a). 

The neuroprotective properties of mild hypothermia have been demonstrated in numerous experimental animal models. Research in this area has been conducted for many years, yet the mechanisms of cerebral protection by mild hypothermia remain unclear and continue to be the subject of intense investigation. The neuroprotective effects of mild hypothermia have been attributed to alterations in metabolic rate (24), neurotransmitter release (25-27), activity of protein kinases (28), resynthesis of cellular repair proteins (29), cerebral blood flow (30), preservation of the blood-brain barrier (BBB) (31), attenuation of inflammatory processes (32,33), and decreases in free radical production (34). Although these may all be components of a complex cascade leading to neurologic injury, it has become increasingly clear that the primary mechanism of action of hypothermia may be different at various temperatures as well as under different ischemic and traumatic conditions. 

What is the evidence that hypothermia plus other potential neuroprotective therapies actually does improve outcome compared with individual neuroprotective agents Surprisingly, there are few preclinical and no human studies that have examined this issue. The main reason for this lack of study likely stems from the added complexity necessary for a combined treatment study, and the desire by most researchers to identify individual agents with neuroprotective properties first before proceeding to evaluate combination treatments. However, a handful of experimental treatment studies have been performed using hypothermia in conjunction with other neuroprotective agents, with surprisingly mixed results. 

There is also evidence that the neuroprotective properties of lipid-peroxidation-inhibiting doses of methylprednisolone, extensively studied in spinal-cord injury, are applicable to brain injury. The steroid has been shown to enhance the early recovery of mice subjected to a moderately severe concussive head injury when administered at 5 minutes post-injury [59], The dose-response curve for this effect is remarkably similar to that discussed above for spinal-cord injury. A 30mg/kg i.v. dose was observed to be optimal, while lower (15 mg/kg) and higher (60 and 120 mg/kg) doses were ineffective. 

HU-211 is highly liposoluble, which makes it readily accessible to the central nervous system since it readily crosses the blood brain barrier. However, its poor solubility in water hampers development of formulations suitable for i.v. administration. In order to overcome this drawback, Popp et al. have prepared a series of water-soluble salts of glycinate esters (attached to the allylic hydroxyl) and salts of amino acid esters containing tertiary and quaternary nitrogen heterocyclics (attached to the phenolic hydroxyl) (see Figure 5.5) [201, 202]. Most of the new compounds were relatively soluble in water or 10% aqueous ethanol, and showed neuroprotective properties, attributed to the parent compound, formed on hydrolysis of the esters in vivo. 

Comments on the generally favorable effects of lithium on immune function have been summarized (46). The antiviral and neuroprotective properties of lithium were mentioned in a review of the immune system and bipolar disorder (47). The potential benefit of lithium in treating AIDS and AIDS-related dementia, owing in part to its cytokine-regulating and neuroprotective effects, has been reviewed (48). Genital Herpes simplex infection has responded to lithium (49). 

The indolocarbazole alkaloids and the biosynthetically related bisindolylmaleiraides constitute an important class of natural products, which have been isolated from actinomycetes, cyanobacteria, slime molds, and marine invertebrates [1-3], They display a wide range of biological activities, including antibacterial, antifungal, antiviral, hypotensive, antitumor, and/or neuroprotective properties. The antitumor and neuroprotective activities of indolocarbazoles are the result of one, or several, of the following mechanisms (a) inhibition of different protein kinases, (b) inhibition of DNA topoisomerases, or (c) direct DNA intercalation [3-6], Hundreds of indolocarbazole derivatives have been produced by chemical synthesis or semisynthesis [1,2,6], and several of them have entered clinical trials for the treatment of diverse types of cancer, Parkinson s disease or diabetic retinopathy [3,7]. 

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