Editing GSK-3 (section)

== Inhibitors ==
Glycogen synthase kinase inhibitors are different [[chemotype]]s and have variable mechanisms of action; they may be [[cation]]s, from natural sources, synthetic ATP and non-ATP competitive inhibitors and substrate-competitive inhibitors. GSK3 is a bi-lobar architecture with [[N-terminal]] and [[C-terminal]], the N-terminal is responsible for ATP binding and C-terminal which is called as [[activation loop]] mediates the kinase activity, Tyrosine located at the C-terminal it essential for full GSK3 activity.<ref name=pmid16452634>{{cite journal | vauthors = Sayas CL, Ariaens A, Ponsioen B, Moolenaar WH | title = GSK-3 is activated by the tyrosine kinase Pyk2 during LPA1-mediated neurite retraction | journal = Molecular Biology of the Cell | volume = 17 | issue = 4 | pages = 1834–1844 | date = April 2006 | pmid = 16452634 | pmc = 1415316 | doi = 10.1091/mbc.E05-07-0688 }}</ref>

===Benefits of GSK-3β inhibitors===
In diabetes, GSK-3β inhibitors increase insulin sensitivity, glycogen synthesis, and glucose metabolism in skeletal muscles, and reduce obesity by affecting the [[adipogenesis]] process.<ref name="pmid23784744" /> GSK-3β is also over expressed in several types of cancers, like [[colorectal cancer|colorectal]], [[Ovarian cancer|ovarian]], and [[prostate cancer]].<ref name=pmid16452634/> GSK-3β inhibitors also aid in the treatment of [[Alzheimer's disease]],{{Citation needed|date=August 2019}} [[stroke]],<ref name="pmid26671619">{{cite journal | vauthors = Wang W, Li M, Wang Y, Li Q, Deng G, Wan J, Yang Q, Chen Q, Wang J | display-authors = 6 | title = GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats | journal = Molecular Neurobiology | volume = 53 | issue = 10 | pages = 7028–7036 | date = December 2016 | pmid = 26671619 | pmc = 4909586 | doi = 10.1007/s12035-015-9607-2 }}</ref> and [[mood disorder]]s, including [[bipolar disorder]].<ref name="pmid18295757">{{cite journal | vauthors = Mohammad MK, Al-Masri IM, Taha MO, Al-Ghussein MA, Alkhatib HS, Najjar S, Bustanji Y | title = Olanzapine inhibits glycogen synthase kinase-3beta: an investigation by docking simulation and experimental validation | journal = European Journal of Pharmacology | volume = 584 | issue = 1 | pages = 185–191 | date = April 2008 | pmid = 18295757 | doi = 10.1016/j.ejphar.2008.01.019 }}</ref> ''In vitro'' studies have shown the beneficial effects of GSK-3 inhibitors in lung cancer,<ref>{{Cite journal |last1=Mathuram |first1=Theodore Lemuel |last2=Venkatesan |first2=Thiagarajan |last3=Das |first3=Jayanta |last4=Natarajan |first4=Umamaheswari |last5=Rathinavelu |first5=Appu |date=August 2020 |title=The apoptotic effect of GSK-3 inhibitors: BIO and CHIR 98014 on H1975 lung cancer cells through ROS generation and mitochondrial dysfunction |url=http://link.springer.com/10.1007/s10529-020-02861-w |journal=Biotechnology Letters |language=en |volume=42 |issue=8 |pages=1351–1368 |doi=10.1007/s10529-020-02861-w |pmid=32236757 |issn=0141-5492}}</ref> ovarian cancer<ref>{{Cite journal |last1=Mathuram |first1=Theodore Lemuel |last2=Ravikumar |first2=Vilwanathan |last3=Reece |first3=Lisa M. |last4=Sasikumar |first4=Changam Sheela |last5=Cherian |first5=Kotturathu Mammen |date=2017 |title=Correlative Studies Unravelling the Possible Mechanism of Cell Death in Tideglusib-Treated Human Ovarian Teratocarcinoma-Derived PA-1 Cells |url=http://www.dl.begellhouse.com/journals/0ff459a57a4c08d0,1b80d9046bc9fa9c,5dda311a012b39ce.html |journal=Journal of Environmental Pathology, Toxicology and Oncology |language=en |volume=36 |issue=4 |pages=321–344 |doi=10.1615/JEnvironPatholToxicolOncol.2017025018 |issn=0731-8898|url-access=subscription }}</ref> and neuroblastoma.<ref>{{Cite journal |last1=Mathuram |first1=Theodore Lemuel |last2=Ravikumar |first2=Vilwanathan |last3=Reece |first3=Lisa M. |last4=Karthik |first4=Selvaraju |last5=Sasikumar |first5=Changam Sheela |last6=Cherian |first6=Kotturathu Mammen |date=September 2016 |title=Tideglusib induces apoptosis in human neuroblastoma IMR32 cells, provoking sub-G 0 /G 1 accumulation and ROS generation |url=https://linkinghub.elsevier.com/retrieve/pii/S1382668916301910 |journal=Environmental Toxicology and Pharmacology |language=en |volume=46 |pages=194–205 |doi=10.1016/j.etap.2016.07.013|pmid=27490211 |url-access=subscription }}</ref>

===Specific agents===
Inhibitors of GSK-3 include:<ref name="pmid31553649">{{cite journal | vauthors = Noori MS, Bhatt PM, Courreges MC, Ghazanfari D, Cuckler C, Orac CM, McMills MC, Schwartz FL, Deosarkar SP, Bergmeier SC, McCall KD, Goetz DJ | display-authors = 6 | title = Identification of a novel selective and potent inhibitor of glycogen synthase kinase-3 | journal = American Journal of Physiology. Cell Physiology | volume = 317 | issue = 6 | pages = C1289–C1303 | date = December 2019 | pmid = 31553649 | pmc = 6962522 | doi = 10.1152/ajpcell.00061.2019 }}</ref><ref name="pmid27902447">{{cite journal | vauthors = Licht-Murava A, Paz R, Vaks L, Avrahami L, Plotkin B, Eisenstein M, Eldar-Finkelman H | title = A unique type of GSK-3 inhibitor brings new opportunities to the clinic | journal = Science Signaling | volume = 9 | issue = 454 | pages = ra110 | date = November 2016 | pmid = 27902447 | doi = 10.1126/scisignal.aah7102 | s2cid = 34207388 }}</ref><ref name="pmid22065134">{{cite journal | vauthors = Eldar-Finkelman H, Martinez A | title = GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS | journal = Frontiers in Molecular Neuroscience | volume = 4 | pages = 32 | year = 2011 | pmid = 22065134 | pmc = 3204427 | doi = 10.3389/fnmol.2011.00032 | doi-access = free }}</ref><ref name="pmid24931005">{{cite journal | vauthors = McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Sokolosky M, Abrams SL, Montalto G, D'Assoro AB, Libra M, Nicoletti F, Maestro R, Basecke J, Rakus D, Gizak A, Demidenko ZN, Cocco L, Martelli AM, Cervello M | display-authors = 6 | title = GSK-3 as potential target for therapeutic intervention in cancer | journal = Oncotarget | volume = 5 | issue = 10 | pages = 2881–2911 | date = May 2014 | pmid = 24931005 | pmc = 4102778 | doi = 10.18632/oncotarget.2037 }}</ref>
{{div col|colwidth=22em}}

===Metal cations===
* [[Beryllium]]
* [[Copper]]
* [[Lithium]] ([[IC50|IC<sub>50</sub>]]=2mM)
* [[Mercury (element)|Mercury]]
* [[Tungsten]] (Indirect)
* [[Zinc]] ([[IC50|IC<sub>50</sub>]]=15μM)

===ATP-competitive===

====Marine organism-derived====
* [[6-BIO]] (IC<sub>50</sub>=1.5μM)
* [[Dibromocantharelline]] (IC<sub>50</sub>=3μM)
* [[Hymenialdesine]] (IC<sub>50</sub>=10nM)
* [[Indirubin]] (IC<sub>50</sub>=5-50nM)
* [[Meridianin]]

====Aminopyrimidines====
* [[CHIR99021]] (IC<sub>50</sub>=6.9nM-10nM)
* [[CHIR98014]] (IC<sub>50</sub>=0.58-0.65nM)
* [[CT98014]]
* [[CT98023]]
* [[CT99021]]
* [[TWS119]] (IC<sub>50</sub>=30nM)

====Arylindolemaleimide====
* [[SB-216763]] (IC<sub>50</sub>=34nM)
* [[SB-41528]] (IC<sub>50</sub>=31-78nM)

====Thiazoles====
* [[AR-A014418]] (IC<sub>50</sub>=104nM)
* [[AZD-1080]] (IC<sub>50</sub>=6.9nM-31nM)

====Paullones====
IC<sub>50</sub>=4-80nM:
* [[Alsterpaullone]]
* [[Cazpaullone]]
* [[Kenpaullone]]

====Aloisines====
IC<sub>50</sub>=0.5-1.5μM:

===Non-ATP competitive===

====Marine organism-derived====
* [[Manzamine A]] (IC<sub>50</sub>=1.5μM)
* [[Palinurine]] (IC<sub>50</sub>=4.5μM)
* [[Tricantine]] (IC<sub>50</sub>=7.5μM)

====Thiazolidinediones====
* [[TDZD-8]] (IC<sub>50</sub>=2μM)
* [[NP00111]] (IC<sub>50</sub>=2μM)
* [[NP031115]] (IC<sub>50</sub>=4μM)
* [[Tideglusib]] (IC<sub>50</sub>=60nM)

====Halomethylketones====
* [[HMK-32]] (IC<sub>50</sub>=1.5μM)

====Peptides====
* [[L803-mts]] (IC<sub>50</sub>=20μM)
* [[L807-mts]] (IC<sub>50</sub>=1μM)

====Unknown Mechanism (small-molecule inhibitors)====
* [[COB-187]] (IC<sub>50</sub>=11nM-22nM)
* [[COB-152]] (IC<sub>50</sub>=77nM-132nM)
{{div col end}}

===Lithium===
Lithium which is used in the treatment of [[bipolar disorder]] was the first natural GSK-3 inhibitor discovered. It inhibits GSK-3 directly by competition with magnesium ions and indirectly by phosphorylation and auto-regulation of serine.
Lithium has been found to have insulin-like effects on glucose metabolism, including stimulation of glycogen synthesis in fat cells, skin, and muscles, increasing glucose uptake, and activation of GS activity. In addition to inhibition of GSK-3, it also inhibits other enzymes involved in the regulation of glucose metabolisms, such as myo-inositol-1-monophosphatase and 1,6 bisphosphatase. Also, it has shown therapeutic benefit in Alzheimer's and other neurodegenerative diseases such as epileptic neurodegeneration.<ref name="pmid22065134" />

===Naproxen and Cromolyn===
Naproxen is a [[Nonsteroidal anti-inflammatory drug|non-steroidal anti-inflammatory drug]] while cromolyn is an [[anti-allergic agent]] which acts as a [[mast cell]] stabilizer. Both drugs have demonstrated the anticancer effect in addition to hypoglycemic effect due to inhibition of glycogen synthase kinase-3β (GSK-3β).

To validate the anti-GSK-3β hypothesis of naproxen and cromolyn, docking of the two structures against GSK-3β binding pocket and comparing their fitting with known GSK-3β inhibitor ARA014418 was performed, in addition to measuring the serum glucose, serum insulin, serum C-peptide, weight variation and hepatic glycogen levels for normal and diabetic fasting animal's models to assess their in vitro hypoglycemic effects.{{Citation needed|date=August 2019}}

Naproxen and cromolyn were successfully docked into the binding site of GSK-3β (both were fitted into its binding pocket). They exhibited electrostatic, hydrophobic, and hydrogen-bonding interactions with key amino acids within the [[binding pocket]] with binding interaction profiles similar to AR-A014418 (the known inhibitor). The negative charges of the carboxylic acid groups in both drugs interact electrostatically with the positively charged guanidine group of Arg141. Moreover, the hydrogen bonding interactions between carboxylic acid moieties of cromolyn and the ammonium groups of Lys183 and Lys60, in addition to π-stacking of the naphthalene ring system of naproxen with the phenolic ring of Tyr134.

Antidiabetic effects of naproxen and cromolyn: In normal animal models, both drugs have shown dose-dependent reduction in blood glucose levels and rise in glycogen levels. In chronic type II diabetic model, glucose levels were also reduced, and glycogen level and insulin levels were elevated in a dose-dependent manner with a reduction in plasma glucose.{{Citation needed|date=August 2019}}

Anti-obesity effects of naproxen and cromolyn: Both drugs showed significant anti-obesity effects as they reduce body weight, resistin, and glucose levels in a dose-dependent manner. They were also found to elevate [[adiponectin]], insulin, and C-peptide levels in a dose-dependent manner.<ref name=pmid23784744>{{cite journal | vauthors = Motawi TM, Bustanji Y, El-Maraghy SA, Taha MO, Al Ghussein MA | title = Naproxen and cromolyn as new glycogen synthase kinase 3β inhibitors for amelioration of diabetes and obesity: an investigation by docking simulation and subsequent in vitro/in vivo biochemical evaluation | journal = Journal of Biochemical and Molecular Toxicology | volume = 27 | issue = 9 | pages = 425–436 | date = September 2013 | pmid = 23784744 | doi = 10.1002/jbt.21503 | s2cid = 46597394 }}</ref>

===Famotidine===
Famotidine is a specific, long-acting [[H2 antagonist]] that decreases gastric acid secretion. It is used in the treatment of peptic ulcer disease, GERD, and pathological hypersecretory conditions, like Zollinger–Ellison syndrome. (14,15) H2-receptor antagonists affect hormone metabolism, but their effect on glucose metabolism is not well established. (16) A study has revealed a glucose-lowering effect for famotidine.{{cn|date=April 2023}}

The study of famotidine binding to the enzyme has showed that famotidine can be docked within the binding pocket of GSK-3β making significant interactions with key points within the GSK-3β binding pocket. Strong hydrogen bond interactions with the key amino acids PRO-136 and VAL -135 and potential hydrophobic interaction with LEU-188 were similar to those found in the ligand binding to the enzyme (AR-A014418).{{citation needed|date=February 2019}}

Furthermore, famotidine showed high GSK-3β binding affinity and inhibitory activity due to interactions that stabilize the complex, namely hydrogen bonding of guanidine group in famotidine with the sulfahydryl moiety in CYS-199; and electrostatic interactions between the same guanidine group with the carboxyl group in ASP-200, the hydrogen bond  between the terminal NH2 group, the OH of the TYR-143, and the hydrophobic interaction of the sulfur atom in the thioether with ILE-62. In vitro studies showed that famotidine inhibits GSK-3β activity and increases liver glycogen reserves in a dose dependent manner. A fourfold increase in the liver glycogen level with the use of the highest dose of famotidine (4.4&nbsp;mg/kg) was observed. Also, famotidine has been shown to decrease serum glucose levels 30, and 60 minutes after oral glucose load in healthy individuals. As a GSK-3β inhibitor, the IC<sub>50</sub> value of famotidine is 1.44μM.<ref>{{cite journal | vauthors = Mohammad M, Al-Masri IM, Issa A, Al-Ghussein MA, Fararjeh M, Alkhatib H, Taha MO, Bustanji Y | display-authors = 6 | title = Famotidine inhibits glycogen synthase kinase-3β: an investigation by docking simulation and experimental validation | journal = Journal of Enzyme Inhibition and Medicinal Chemistry | volume = 28 | issue = 4 | pages = 690–694 | date = August 2013 | pmid = 22512725 | doi = 10.3109/14756366.2012.672413 | s2cid = 11890710 | doi-access = free }}</ref>

===Curcumin===
Curcumin, which Is a constituent of [[turmeric]] spice, has flavoring and coloring properties.<ref>{{cite journal | vauthors = Maheshwari RK, Singh AK, Gaddipati J, Srimal RC | title = Multiple biological activities of curcumin: a short review | journal = Life Sciences | volume = 78 | issue = 18 | pages = 2081–2087 | date = March 2006 | pmid = 16413584 | doi = 10.1016/j.lfs.2005.12.007 }}</ref> It has two symmetrical forms: enol (the most abundant forms) and ketone.<ref>{{cite journal | vauthors = Balasubramanian K | title = Molecular orbital basis for yellow curry spice curcumin's prevention of Alzheimer's disease | journal = Journal of Agricultural and Food Chemistry | volume = 54 | issue = 10 | pages = 3512–3520 | date = May 2006 | pmid = 19127718 | doi = 10.1021/jf0603533 | bibcode = 2006JAFC...54.3512B }}</ref><ref>{{cite journal | vauthors = Payton F, Sandusky P, Alworth WL | title = NMR study of the solution structure of curcumin | journal = Journal of Natural Products | volume = 70 | issue = 2 | pages = 143–146 | date = February 2007 | pmid = 17315954 | doi = 10.1021/np060263s | bibcode = 2007JNAtP..70..143P }}</ref>

Curcumin has wide pharmacological activities: anti-inflammatory,<ref>{{cite journal | vauthors = Kohli K, Ali J, Ansari MJ, Raheman Z |doi=10.4103/0253-7613.16209 |title=Curcumin: A natural antiinflammatory agent |journal=Indian Journal of Pharmacology |volume=37 |issue=3 |pages=141 |year=2005 |url=http://www.bioline.org.br/pdf?ph05037 |doi-access=free |hdl=1807/8668 |hdl-access=free }}</ref> anti-microbial,<ref>{{cite journal | vauthors = Negi PS, Jayaprakasha GK, Jagan Mohan Rao L, Sakariah KK | title = Antibacterial activity of turmeric oil: a byproduct from curcumin manufacture | journal = Journal of Agricultural and Food Chemistry | volume = 47 | issue = 10 | pages = 4297–4300 | date = October 1999 | pmid = 10552805 | doi = 10.1021/jf990308d | bibcode = 1999JAFC...47.4297N }}</ref> hypoglycemic, anti-oxidant, and wound healing effects.<ref>{{cite journal | vauthors = Sidhu GS, Singh AK, Thaloor D, Banaudha KK, Patnaik GK, Srimal RC, Maheshwari RK | title = Enhancement of wound healing by curcumin in animals | journal = Wound Repair and Regeneration | volume = 6 | issue = 2 | pages = 167–177 | year = 1998 | pmid = 9776860 | doi = 10.1046/j.1524-475X.1998.60211.x | s2cid = 21440334 }}</ref> In animal models with Alzheimer disease, it has anti-destructive effect of beta amyloid in the brain,<ref>{{cite journal | vauthors = Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM | display-authors = 6 | title = Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo | journal = The Journal of Biological Chemistry | volume = 280 | issue = 7 | pages = 5892–5901 | date = February 2005 | pmid = 15590663 | doi = 10.1074/jbc.M404751200 | doi-access = free }}</ref> and recently it shows anti-malarial activity.<ref>{{cite journal | vauthors = Mishra S, Karmodiya K, Surolia N, Surolia A | title = Synthesis and exploration of novel curcumin analogues as anti-malarial agents | journal = Bioorganic & Medicinal Chemistry | volume = 16 | issue = 6 | pages = 2894–2902 | date = March 2008 | pmid = 18194869 | doi = 10.1016/j.bmc.2007.12.054 }}</ref>

Curcumin also has chemo preventative and anti-cancer effects,{{cn|date=September 2024}} and it has been shown to attenuate oxidative stress and renal dysfunction in diabetic animals with chronic use.<ref>{{cite journal | vauthors = Sharma S, Kulkarni SK, Chopra K | title = Curcumin, the active principle of turmeric (Curcuma longa), ameliorates diabetic nephropathy in rats | journal = Clinical and Experimental Pharmacology & Physiology | volume = 33 | issue = 10 | pages = 940–945 | date = October 2006 | pmid = 17002671 | doi = 10.1111/j.1440-1681.2006.04468.x | s2cid = 25193929 }}</ref>

Curcumin's mechanism of action is anti-inflammatory; it inhibits the nuclear transcriptional activator kappa B ([[NF-κB|NF-KB]]) that is activated whenever there is inflammatory response.{{citation needed|date=February 2019}}

[[NF-kB]] has two regulatory factors, IkB and GSK-3,<ref>{{cite journal | vauthors = Demarchi F, Bertoli C, Sandy P, Schneider C | title = Glycogen synthase kinase-3 beta regulates NF-kappa B1/p105 stability | journal = The Journal of Biological Chemistry | volume = 278 | issue = 41 | pages = 39583–39590 | date = October 2003 | pmid = 12871932 | doi = 10.1074/jbc.M305676200 | doi-access = free }}</ref> which suggests curcumin directly binds and inhibits GSK-3B. An in vitro study confirmed GSK-3B inhibition by simulating molecular docking using a silico docking technique.<ref name="Bustanji_2009">{{cite journal | vauthors = Bustanji Y, Taha MO, Almasri IM, Al-Ghussein MA, Mohammad MK, Alkhatib HS | title = Inhibition of glycogen synthase kinase by curcumin: Investigation by simulated molecular docking and subsequent in vitro/in vivo evaluation | journal = Journal of Enzyme Inhibition and Medicinal Chemistry | volume = 24 | issue = 3 | pages = 771–778 | date = June 2009 | pmid = 18720192 | doi = 10.1080/14756360802364377 | s2cid = 23137441 }}</ref> The concentration at which 50% of GK-3B would be inhibited by curcumin is 66.3 nM.<ref name="Bustanji_2009" />

Among its two forms, experimental and theoretical studies show that the enol form is the favored form due to its intra-molecular hydrogen bonding, and an NMR experiment show that enol form exist in a variety of solvents.{{citation needed|date=February 2019}}

===Olanzapine===
[[Antipsychotic]] medications are increasingly used for [[schizophrenia]], bipolar disorder, anxiety, and other psychiatric conditions<ref>{{cite web |publisher=Mind.org.uk |year=2018 |title=Antipsychotics A-Z |url=https://www.mind.org.uk/information-support/drugs-and-treatments/antipsychotics-a-z }}{{MEDRS|date=February 2019}}</ref> Atypical antipsychotics are more commonly used than first generation antipsychotics because they decrease the risk of extrapyramidal symptoms, such as [[tardive dyskinesia]], and have better efficacy.<ref name=WebMD>{{cite web |title=Antipsychotic Medication for Bipolar Disorder |publisher=WebMD |url=https://www.webmd.com/bipolar-disorder/guide/antipsychotic-medication }}</ref>

Olanzapine and atypical antipsychotics induce weight gain through increasing body fat.<ref>{{cite journal | vauthors = Goudie AJ, Smith JA, Halford JC | title = Characterization of olanzapine-induced weight gain in rats | journal = Journal of Psychopharmacology | volume = 16 | issue = 4 | pages = 291–296 | date = December 2002 | pmid = 12503827 | doi = 10.1177/026988110201600402 | s2cid = 23589812 }}</ref> It also affects glucose metabolism, and several studies shows that it may worsen diabetes.<ref>{{cite journal | vauthors = Di Lorenzo R, Brogli A | title = Profile of olanzapine long-acting injection for the maintenance treatment of adult patients with schizophrenia | journal = Neuropsychiatric Disease and Treatment | volume = 6 | pages = 573–581 | date = September 2010 | pmid = 20856920 | pmc = 2938306 | doi = 10.2147/NDT.S5463 | doi-access = free }}</ref>

A recent study shows that olanzapine inhibits GSK3 activity, suggesting olanzapine permits glycogen synthesis.  A study of the effect of olanzapine on mouse blood glucose and glycogen levels showed a significant decrease in blood glucose level and elevation of glycogen level in mice, and the IC50% of olanzapine were 91.0&nbsp;nm, which is considered a potent inhibitor. The study also illustrates that sub-chronic use of olanzapine results in potent inhibition of GSK3.<ref name=pmid18295757/>

===Pyrimidine derivatives===
[[Pyrimidine analogue]]s are antimetabolites that interfere with nucleic acid synthesis.<ref>{{cite book |doi=10.1016/B978-0-444-59499-0.00045-3 |chapter=Cytostatic and cytotoxic drugs |title=A worldwide yearly survey of new data in adverse drug reactions and interactions |volume=34 |pages=731–747 |series=Side Effects of Drugs Annual |year=2012 | vauthors = Murphy F, Middleton M |isbn=978-0-444-59499-0 }}</ref> Some of them have been shown to fit the ATP-binding pocket of GSK-3β to lower blood glucose levels and improve some neuronal diseases.<ref>{{cite journal | vauthors = Kramer T, Schmidt B, Lo Monte F | title = Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer's Disease Models | journal = International Journal of Alzheimer's Disease | volume = 2012 | pages = 381029 | year = 2012 | pmid = 22888461 | pmc = 3408674 | doi = 10.1155/2012/381029 | doi-access = free }}</ref>