Perzinfotel (EAA-090) is a novel squaric acid amide derivative that has been identified as a potential treatment for ischemic brain damage resulting from stroke. EAA-090 is a competitive inhibitor at the NMDA-selective subtype of the glutamate receptor. The compound demonstrates potent inhibitory activity in both in vitro and in vivo models of NMDA-induced excitotoxicity and provides neuroprotective efficacy in several animal models of stroke. EAA-090 is unique among competitive NMDA antagonists in displaying a clear separation between predicted efficacious dose and doses that induce PCP-like psychotomimetic side effects in both animals and humans. This unique profile makes EAA-090 an exciting candidate for assessing the neuroprotective potential of the competitive NMDA mechanism.

Flindokalner (BMS 204352; MaxiPost™) is a neuroprotective agent with potential in the treatment of stroke developed by Bristol-Myers Squibb. Flindokalner is a potent and effective opener of two important subtypes of neuronal potassium channels, the calcium-activated, big-conductance potassium channels (K(Ca) channels) and voltage-dependent, non-inactivating potassium channels known as KCNQ channels. Flindokalner significantly reduced cortical infarct volume in a animal models of stroke. Flindokalner failed to show superior efficacy in acute stroke patients compared to placebo in a Phase III study.

Smoothened agonist (SAG), a chlorobenzothiophene-containing Hh pathway agonist, was shown to be able to bind directly to Smo and activate Shh-dependent pathway. SAG and similar compounds represent attractive molecules to be developed for treatment of disorders where stimulation of the generation and survival of new neural cells would be beneficial. Thus, it was demonstrated that small-molecule agonist of Smo has potential as a neuroprotective agent in neonates at risk for glucocorticoid-induced neonatal cerebellar injury. Moreover, hedgehog agonist therapy corrects structural and cognitive deficits in a Down syndrome mouse model.

(S)-Seliciclib is enantiomer of the potent cyclin-dependent kinase (CDK) inhibitor Roscovitine. Roscovitine (racemic mixture) is an inhibitor of cell cyclin-dependent kinase (CDK)-2, CDK-4 and CDK-5, which are upregulated in stress conditions inducing apoptosis. (S)-Seliciclib potently inhibits Cyclin-dependent kinase 1. In vivo studies in rabbits demonstrated that both isomers (R- and S-) significantly reduce intraocular pressure (IOP). However, S- isomer was superior to R- isomer in lowering IOP and providing protection to retinal ganglionic cells.

PJ34 is PARP inhibitor. It protects primary neuronal cells from oxygen-glucose deprivation in vitro and reduces infarct size following cerebral and cardiac ischemia in vivo. PJ34 exhibit suppresses cell growth and enhances the suppressive effects of cisplatin in liver cancer cells.

Neopterin is a byproduct of the tetrahydrobiopterin (BH4) biosynthetic pathway, which requires Mg2+, Zn2+, and NADPH as cofactors. Tetrahydrobiopterin is an obligatory cofactor for phenylalanine, tyrosine, tryptophan hydroxylases and alkylglycerol monooxygenase, and for all isoforms of nitric oxide synthase (NOS). BH4 is synthesized by multiple metabolic routes, namely the de novo, salvage and recycling pathways. The de novo via generates BH4 from guanosine triphosphate (GTP) by the concert action of guanosine triphosphate Cyclohydrolase I (GTPCH), 6-pyruvoyl Tetrahydropterin synthase (PTPS) and sepiapterin reductase. GTPCH catalyzes the conversion of GTP to 7,8-dihydroneopterin triphosphate. Then, Alkaline Phosphatases removes the phosphates to generate, 8-dihydroneopterin, which is further converted to Neopterin by non-enzymatic oxidation. Neopterin is a recognized biomarker for immune system activation. IFN-g, which is released from activated Th1 cells during the initiation of the immunological cellular response, is one of the main stimuli for neopterin formation. The source of neopterin in the central nervous system (CNS) is not well understood. The evidence available in the literature has suggested that neopterin crosses the blood-brain barrier, therefore the CSF levels may reflect the serum or plasma neopterin concentrations. Cell culture studies strongly suggest that neopterin is not an inert compound, but a cytoprotective molecule synthesized and secreted by nerve cells as a response to damage or inflammation.

AM-36 is a novel arylalkylpiperazine with combined antioxidant and Na(+) channel blocking actions. This compound was discovered as a four-year Amrad-funded program with the Departments of Pharmacology and Chemistry at Monash University. In preclinical studies was shown, that AM-36 might have great promise in the acute treatment of human stroke. But these investigation were discontinued.

Ginkgolide A (GA, BN52020), is a terpene lactone constituent of Ginkgo biloba, the ginkgo tree, is the oldest living tree, with a long history of use in traditional Chinese medicine. Ginkgolide A is an effective antagonist of platelet activating factor, an ubiquitous phospholipid that acts as a mediator of numerous pathophysiological conditions. Ginkgolide A displays anxiolytic, antiinflammatory properties, protects from cerebral ischemia in animal models.

Perlonguminine is an alkaloid amide isolated from species of the genus Piper, a plant used in traditional medicine that demonstrates antifungal, anticancer, antihyperlipidemic, and anti-inflammatory properties. Perlonguminine selectively targets a wide spectrum of cancer cells and induce cancer cell death by initiating various pathways, such as apoptosis, necrosis, and autophagy. The elevation of reactive oxygen species (ROS), characteristic of oxidative stress, is an important mechanism by which Perlonguminine promotes cancer-selective cell death. However, the poor aqueous solubility of Perlonguminine is a serious concern for intensive investigations and clinical application.

Linoleic monoethanolamide (or linoleoyl ethanolamide), an endocannabinoid, which weakly binds to CB1 and CB2 receptors. It was used as a neuroprotective agent in a rat model for stroke and acted through an intracellular mechanism independent of the classic endocannabinoid pathways. In addition, was shown, that linoleoyl ethanolamide was not useful in assessing pain in patients with chronic pancreatic diseases and it couldn’t replace a simple method such as a visual analogic scale for assessing the pain and its intensity.