Clausenamide

2022-05-19: Nootropics reference: https://old.reddit.com/r/NooTopics/comments/s7lq9m/clausenamide_herbal_piracetam/

Clausenamide #

• Blocks acetaminophen-induced liver ferroptosis in vitro/vivo. Reduces lipid peroxidation, increases GPX4 expression
• The anti-dementia drug candidate, (−)-clausenamide, improves memory impairment through its multi-target effect (2016) #Read
  • Mild elevation of intracellular Ca2+ concentrations -> neuron survival + outgrowth & antagonism of neural apoptosis induced by growht factor deprivation.
    • Intracellular Ca2+ levels are mainly regulated by the following factors: (1) extracellular Ca2+ influx into the cytoplasm, (2) Ca2+ release from intracellular stores, (3) Ca2+ clearance via either outflow from the cytoplasm to the extracellular space or accumulation into internal Ca2+ stores, and (4) cytoplasmic Ca2+ buffering.
  • Modulation of the cholinergic system
    • In vitro promotion of ChAT in frontal cortex neurons -> suppored cholinergic neuron survival + neurite outgrowth & synaptosomal ACh release.
    • In vivo: Increased ChAT in the neocortex, hippicampus, and sitratum: [Effects of (-), (+)clausenamide on anisodine-induced acetylcholine decrease and associated memory deficits in the mouse brain (1998)]. reversibly inhibited ACE with much lower potency than inhibitors like galantamine.
  • Upregulation of synaptic plasticity
    • There are two forms of LTP in the hippocampus: N-Methyl-D-aspartate-(NMDA-) or VGCC-dependent LTP. Clau induced the latter. LTP is not inhibited by nimodipine, indicating VGCC (potentiation) is only necessary for induction but not maintenaince.
    • Did not bind to NMDAR, indicating it is NMDAR independent: [Effects of (-), (+) clausenamide on central N-methyl-D-asparate receptors in rodents (1997)].
    • APV, an NMDAR blocker, had no effect on clau-induced LTP: [Two forms of long-term potentiation induced by different compounds (Xu et al 2007)]
    • However, chronic administration of clau promoted the expression of synaptic NMDA receptors:
      • (1) increasing NMDA receptor density in synaptic membranes,
      • (2) increasing NMDA receptor affinity to their endogenous ligands as indicated by the (-)-clau-increased Bmax values of NMDA receptors in the synaptic membrane, and
      • (3) ameliorating oxidative stress-induced synaptic membrane fluidity, which facilitates NMDA receptor turnover in synaptic membrane.
    • Increased mossy fiber sprouting and expression of GAP43
  • Activation of cellular and molecular signaling pathways involved in learning and memory.
  • Inhibits Tau hyperphorsphorylation and Amyloid β -inducde intracellular Ca2+ overload.
    • APP mice are generated by overexpression of the mutant APP gene and are characterized by senile plaque overload and related apoptosis in the central nervous system.
    • There’s a Chinese study out there where it improved symptoms in human Alzheimer’s patients - 400mg/week, once a week.
    • Anti-apoptotic in five regards:
      • (1) low potassium in cerebellar granule cells, (2) growth factor deprivation in cortical neurons,
      • (3) 6-OHDA in high BAXα-expressing PC12 cells,
        • Inhibited BAX-α-induced cytochrome C release, possibly by increasing glutathione content?
      • (4) ischemia/reperfusion in rats, and (5) Aβ1-40 infusion- and natural aging in rat brain*
      • Inhibits expression of p53, c-Myc, etc.
      • PKC-MEK negatively regulates GSK-3β (-> Tau hyperphosphorylation.) Akt and mitogen-activated protein kinase enhance C-type lectin-like receptor 2-mediated platelet activation by inhibition of glycogen synthase kinase 3α/β (CLEC-2 and GPVI (potentiated by AKT/MAPK:) activate platelets through Src, Syk, and PLCγ-2)
        • And Clau surely increases PKC, which was shown in Xu 2005. Clau-induced microtubule protection was at least in part mediated by PP1, responsible for tau dephosphorylation.
  • They go relatively in-depth regarding its chemistry. Its nootropic effects are chirality-dependent. Clau was more potent than piracetam (5-10mg/kg vs. 500mg/kg respectively) for improving performance in memory-impaired animals.
• Previously, Recent advances in the study of (–)clausenamide: chemistry, biological activities and mechanism of action (Oct 2014) #Read
  • NGF & BDNF induce small elevations of Ca2+ in neurons
  • Shown to be a potassium channel antagonist (preventing efflux) and inducing membrane depolarization.
• (−)Clausenamide facilitates synaptic transmission at hippocampal Schaffer collateral-CA1 synapses (2012) #Read
  • Calcium release from endoplasmic reticulum is mediated by two main types of receptors: RyRs and IP3-Rs.. Ryanodine blockage of RyR suppressed synaptic facilitation, whereas IP3 blockage showed no effect, suggesting even PLC might not even be involved.
  • CAMKII dependent.
  • PKA inhibitor: no effect.
  • So it’s turning out to be a slightly exotic cascade, I guess. VGCC -> RyR -> CAMKII -> CREB -> Egr1, BDNF, etc. - CAMKII -> p-ERK peaked 5 and 30 minutes in hippocampus and cortex respectively. p-nCREB 9 minutes after.
• Study on the Nootropic Mechanism of (-)Clausenamide - Influence on the Formation of Synapses in Mouse Brain (Jiang & Zhang (1998/2006) #Read (short)
  • Increased cortical thickness by 10% in 4 weeks.
    • Gintrux links this for demonstrating cortical thickness and intelligence: Cognitive ability changes and dynamics of cortical thickness development in healthy children and adolescents (2013)
    • Coul.d be due to intracellular Ca2+ influencing neuronal cytoarchitecture.
  • 29% growth of synapse density in a region of the CA3.
• (
  )-Clausenamide Potentiates Synaptic Transmission in the Dentate Gyrus of Rats (Xu et al 2005) #Read
• Physiological signature of a novel potentiator of AMPA receptor signalling (Szulc et al., 2018) not even chinese
  • We have synthesized a novel small molecule based on the pyrrolidinone–containing core structure of Clausenamide.: BRS-015
  • Overall quite similar to clausenamide; no NMDAR effects, chirality, etc. They hypothesize AMPA potentiation is via CAMKII -> γ-8.
  • Potentiated inward currents evoked by local application of l–glutamate onto CA3. It facilitated the induction of mossy fibre LTP, but the magnitude of potentiation was smaller than that observed in untreated slices.
  • Asymmetrical synapses between large mossy fibre terminals and thorny excrescences in CA3 pyramidal neurons contain an average number of AMPA receptors exceeding 4 times the number reported for C/A synapses.
    • [Age-dependent pre- and postsynaptic distribution of AMPA receptors at synapses in CA3 stratum radiatum of hippocampal slice cultures compared with intact brain]
    • Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus (1998)
  • C/A (not CA) synapses can be void of AMPAR, while mossy fibre synapses have smaller variability.
  • High-resolution immunogold localization of AMPA type glutamate receptor subunits at synaptic and non-synaptic sites in rat hippocampus
    • Higher GluR1 expression at A/C (associational/commissural synapses) synapses, compared to mossy fibre synapses which have subtypes more equally.
      • Well that’s a whole other rabbithole.
• [Activation of ERK1/2-CREB pathway during potentiating synaptic transmission of (-)clausenamide in rat dentate gyrus. (2012)]
• Increases Choline Acetyltransferase.
• Gintrux:The cortex begins to thin after the age of five or six as part of the normal aging process. This study is the first to show the association between cortical thickness and development in full scale IQ, and has potentially wide-ranging implications for the pedagogical world and for judicial cases in which the defendant’s IQ score could play a role in determining the severity of the sentence
  • Could this be a correlate for the cut-off point for Intelligence?

Dose #

• $1k for 60g. Probably don’t need more than a few grams.
• Orally bioavailable. Probably CYP3A as the predominant isoform.