GSK3b inhibition is one of my favorite pathways for enhancement.
What is GSK3B?
GSK3B (Glycogen synthase kinase 3 beta) is an enzyme associated with energy metabolism, neuronal cell development, and body pattern formation .
GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer’s and bipolar disorder .
Glycogen synthase kinase 3 (GSK-3) acts as an essential “brake” on many growth-signaling pathways including Wnt and insulin. GSK-3 has high activity in resting tissues and is inhibited upon cellular stimulation .
Benefits of GSK3B Inhibition
GSK3B inhibition may reduce the formation of amyloid plaques, a hallmark of Alzheimer’s .
2) Obesity and Type 2 Diabetes
Glycogen synthase kinase-3 (GSK-3) has important roles in the regulation of glycogen synthesis, protein synthesis, gene transcription, and cell differentiation in various cell types .
Increased GSK3 has been reported in type II diabetics and obese animal models .
Inhibitors of GSK3 have been demonstrated to have anti-diabetic effects in test tubes and animal models .
Overexpression and overactivity of GSK-3 in the muscle of rodent models of obesity and type 2 diabetic humans are associated with an impaired ability of insulin to activate glucose disposal and glycogen synthase .
Inhibitors of GSK3B activity improve insulin response and maintain proper glucose levels .
In muscle, GSK3b inhibits glycogen synthesis .
Inhibitors of GSK3B activity could be useful in prostate, glioblastoma, neuroblastoma, pancreatic, and colorectal cancer .
GSK3B promotes ovarian cancer cell proliferation and chemotherapy resistance .
Inhibitors of GSK3B could be useful in prostate cancer therapy .
Pancreatic cancer cells contain a pool of active GSK3B, and inhibition of GSK3B leads to decreased cancer cell proliferation and survival .
Colon cancer cells from patients have higher levels of GSK3B expression than their normal counterparts .
4) Mood: Depression and Anxiety
Increased GSK3B activity has been reported as a state marker of major affective episodes in patients with depression and bipolar disorder.
Elderly depressed patients had significantly higher GSK3B activity. Higher GSK3B activity was observed in patients with severe depressive episodes and with cognitive impairment .
5) Inflammation and Pain
Inhibitors of GSK3β have been shown to be beneficial in many neuroinflammatory disease models including Alzheimer’s disease, multiple sclerosis and AIDS dementia complex .
GSK3-β induces TLR-mediated excessive inflammatory responses in the gut .
Blockade of GSK3-β attenuates excessive proinflammatory TLR-mediated immune responses. GSK3-β inhibition, therefore, constitutes a promising therapeutic option for selectively reducing exaggerated intestinal immune reactions toward the luminal flora in inflammatory bowel disease .
Inhibitors of GSK3b stop neuroinflammation and pain .
Inhibition of GSK3β in cells leads to suppression of Toll-like receptor (TLR)-initiated proinflammatory cytokines from NfkB.
GSK3b increases NfkB .
6) Sociability and Resilience
GSK3 inhibition (hippocampus and striatum) increases resilience to defeat and decreases responsiveness to psychostimulants .
7) Nootropic Effects
Studies have found increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer’s disease .
GSK3 is critical for brain development and neuroplasticity, which appear to be interrelated and to mediate age-associated neurological diseases .
Specifically, GSK3 plays a pivotal role in controlling neuronal progenitor proliferation and establishment of neuronal polarity during development, and neuronal GSK3 function affects neuroplasticity throughout the lifespan .
GSK3 is proposed to be a therapeutic target for the restoration of synaptic functioning and cognition .
GSK3β inhibition stimulates the regeneration of myelin-forming cells and remyelination following chemically induced demyelination .
GSK3b inhibition stimulates axon regeneration in injured cortical connections .
Damaged axons in the adult central nervous system normally do not regenerate after lesion, largely because of the presence of growth inhibitory molecules at the scar .
Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice .
Mice injected with cocaine (20 mg/kg, i.p) showed an increase in the activity of GSK3β in the caudate putamen.
GSK3b inhibitors produced significant dose-dependent reductions in cocaine-induced activity .
GSK3 activity status is regulated by the circadian clock and GSK3 feeds back to regulate the molecular clock amplitude in the Suprachiasmatic Nucleus .
Glycogen synthase kinase 3 (GSK3) interacts with at least 5 core clock proteins and shows daily variation itself. Significant circadian rhythmicity of phosphorylated GSK3 (α and β) was observed in the SCN .
GSK3b increases Rev-Erb-a while helping to break down ARNTL/BMAL1, CLOCK, and PER2 .
Top GSK3 beta Inhibitors
- Lithium (potent, IC50=1-2mM, but actual inhibition is more in-vivo) [26, 24]
- Zinc (potent, IC50 = 15 μM) 
- Copper (potent) [26, 27]
- Curcumin (very potent, IC50=66nM) 
- Butyrate [30+]
- Quercetin (potent, IC50=2.0 μM) 
- Luteolin (potent, IC50=1.5 μM) 
- Apigenin (potent, IC50=1.9 μM) 
- Astaxanthin 
- Cinnamon 
- Angelica Sinensis 
- Berberine 
- Resveratrol 
- SSRIs 
- Ketamine 
- Trichostatin [30+]
- Valproic Acid 
- Intranasal insulin (normalized high GSK3b in diabetic animals) 
What Increases GSK3b?
Genetics and GSK3B
The most important SNPs in GSK3B are:
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