Lithium is an alkali metal widely used in industry. Lithium salts are indicated in the treatment of manic episodes of Bipolar Disorder. The use of lithium in psychiatry goes back to the mid-19th century. Early work, however, was soon forgotten, and John Cade is credited with reintroducing lithium to psychiatry for mania in 1949. Mogens Schou undertook a randomly controlled trial for mania in 1954, and in the course of that study became curious about lithium as a prophylactic for depressive illness. In 1970, the United States became the 50th country to admit lithium to the marketplace. The specific mechanisms by which lithium exerts its mood-stabilizing effects are not well understood. Lithium appears to preserve or increase the volume of brain structures involved in emotional regulation such as the prefrontal cortex, hippocampus and amygdala, possibly reflecting its neuroprotective effects. At a neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases inhibitory (GABA) neurotransmission; however, these broad effects are underpinned by complex neurotransmitter systems that strive to achieve homeostasis by way of compensatory changes. For example, at an intracellular and molecular level, lithium targets second-messenger systems that further modulate neurotransmission. For instance, the effects of lithium on the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C, may serve to dampen excessive excitatory neurotransmission. In addition to these many putative mechanisms, it has also been proposed that the neuroprotective effects of lithium are key to its therapeutic actions. In this regard, lithium has been shown to reduce the oxidative stress that occurs with multiple episodes of mania and depression. Further, it increases protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma 2, and reduces apoptotic processes through inhibition of glycogen synthase kinase 3 and autophagy.

Luteolin, 3',4',5,7-tetrahydroxyflavone, is a common flavonoid that exists in many types of plants including fruits, vegetables, and medicinal herbs. Plants rich in luteolin have been used in Chinese traditional medicine for treating various diseases such as hypertension, inflammatory disorders, and cancer. Luteolin possesses a variety of pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial and anticancer activities. Numerous studies have shown that luteolin possesses beneficial neuroprotective effects both in vitro and in vivo.

CHIR 99021 is a selective, pyridimidine-based, glycogen synthase kinase 3 inhibitor that is effective at low nanomolar concentrations in enzyme assays and submicromolar concentrations in isolated cells and tissues. Chiron was developing CHIR 99021 for potential use in the treatment of type 2 diabetes mellitus. CHIR 99021 promoted insulin-mediated glucose uptake and increased glucose disposal in rodent models of diabetes. However, there has been no recent development reported.

Tideglusib (NP031112, NP-12, Nypta, Noscira SA, Madrid, Spain), a drug, which belongs to the thiadiazolidinone family, is a GSK-3β inhibitor. Tideglusib was in phase II clinical trials for the treatment of Alzheimer disease (AD) and progressive supranuclear palsy. Participants showed no benefit on either of the primary outcome measures or exploratory endpoints and further development in the drug was halted for these two disease. However, Tideglusib is on phase II clinical trial to determine whether drug is safe and efficacious in the treatment of adolescents and adults with congenital and juvenile-onset Myotonic Dystrophy.

JNJ-872 is an inhibitor of influenza virus replication that offers a potential for the treatment of pandemic and seasonal influenza.

AT-9283 was being developed by Astex Pharmaceuticals as a treatment for cancer and myelofibrosis. AT-9283 is an inhibitor of mitosis (cell division) and is the second most progressed drug candidate in the Astex portfolio of novel molecularly targeted cancer drugs. All of Astex’s current products have been discovered internally using its proprietary drug discovery approach. AT9283 is a potent inhibitor of the Aurora A and B kinases and has been shown to arrest tumour growth in a range of tumour models. Aurora kinases play a key role in mitotic checkpoint control in cell division. Both Aurora A and B are over-expressed in many human tumours and are believed to be excellent targets for anti-cancer therapy.

LY-2090314 is a GSK-3alpha and GSK-3beta inhibitor developed by Eli Lilly. Phase 2 clinical trials of LY-2090314 as a signle agenst against acute leukemia did not show clinical benefit. LY-2090314 was studied in combination pemetrexed and carboplatin against solid tumors, and in combination with FOLFOX, gemcitabine, and nab-paclitaxel against pancreatic cancer.

AZ-1080 (AZD-1080) is an inhibitor of GSK-beta which was developed by AstraZeneca and initially tested in patients with Alzheimer’s disease (phase I). The drug was discontinued for the aforementioned condition, but now it is being investigated as a potential therapy for ovarina cancer and emdometrial carcinoma (basic research).

AstraZeneca was developing the thiazole AR-AO-14418, a selective inhibitor of glycogen synthase kinase 3β (GSK-3β), for the treatment of Alzheimer's disease and major depressive disorder. AR-AO-14418 is an important research tool in as much as, at concentrations that AR-AO-14418 is able to inhibit GSK3 activity, this compound did not affect the activity of other 26 protein kinases tested, and especially does not inhibit cdc2 and cdk5, two GSK3-related kinases that are inhibited by published GSK3 inhibitors. Furthermore, AR-AO-14418 constitutes a lead compound with therapeutic potential for the treatment of AD, as well as other neurodegenerative disorders. Later preclinical studies of AR-AO-14418 were discontinued.

Staurosporine is an alkaloid isolated from the culture broth of Streptomyces staurosporesa. It exerts antimicrobial, hypotensive, and cytotoxic activity. The main biological activity of staurosporine is the inhibition of protein kinases through the prevention of ATP binding to the kinase. This is achieved through the stronger affinity of staurosporine to the ATP-binding site on the kinase. Staurosporine is a prototypical ATP-competitive kinase inhibitor in that it binds to many kinases with high affinity, though with little selectivity. It is a potent, cell permeable protein kinase C inhibitor with an IC50 of 0.7 nM. At higher concentration (1-20 nM), staurosporine also inhibits other kinases such as PKA, PKG, CAMKII and Myosin light chain kinase (MLCK). At 50-100 nM, it is a functional neurotrophin agonist, promoting neurite outgrowth in neuroblastoma, pheochromocytoma and brain primary neuronal cultures. At 0.2- 1 uM, staurosporine induces cell apoptosis. Staurosporine is also a potent GSK-3β inhibitor with a reported IC50 value of 15 nM. In research, staurosporine is used to induce apoptosis. It has been found that one way in which staurosporine induces apoptosis is by activating caspase-3. Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive. The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment. Staurosporine induces apoptosis by multiple pathways and that the inhibition of more than one kinase is responsible for its potent activity. Because the mechanism of action of staurosporine is distinct from traditional anticancer drugs, this may warrant further preclinical evaluations of the antitumor potential of new staurosporine derivatives either alone or in combination with death ligands or conventional chemotherapeutic drugs.