Istradefylline

2022-12-15:

Istradefylline (KW-6002) #

• A2A antagonist. Wikipedia mentions how this eventually leads to D2 disinhibition, and so does brenden’s anecdotes.
  • Disrupting A2A-CB1 heterodimers will actually upregulate CB1.
• Weak CYP3A4 inducer (in vitro)? Metabolized by CYP1A1, CYP3A4, CYP3A5.
• Istradefylline, an adenosine A2a receptor antagonist, inhibits the CD4+ T-cell hypersecretion of IL-17A and IL-8 in humans
• Doesn’t even affect sleep: Istradefylline improves daytime sleepiness in patients with Parkinson’s disease: An open-label, 3-month study
• JC says it will have an additive effect on striatal dopamine and partially restoring normal frontal DA (I guess that depends on parkinson’s/excess GDNF as in the study) whereas it’s guanfacine that will really balance out striatal and frontal.
• Lack of tolerance to motor stimulant effects of a selective adenosine A(2A) receptor antagonist
  • No change in A1, A2A, D1, D2 or their mRNA.
• [Istradefylline is recommended for morning use: a report of 4 cases.] #Read
• Role of adenosine A2A receptors in hot and cold cognition: Effects of single-dose istradefylline in healthy volunteers (20mg) #Read (pretty much)
  • Subjects on istradefylline interpreted social situations more positively (Social Information Preference)
  • Effected risk adjustment loss on the cambridge gamble task (which is interesting, I suppose. It activates OFC)
  • … we did not detect any other effects across a variety of hot and cold cognitive domains
  • Habitual coffee drinkers display a distinct pattern of brain functional connectivity
    • Higher stress levels, and associated with anxiety in males. Decreased functional connectivity in a network encompassing subcortical and posterior brain regions associated wtih somatosensory, motor, and emotional processing.
  • Learning and cognitive flexibility: frontostriatal function and monoaminergic modulation
  • Dopamine and Cognitive Control in Prefrontal Cortex
    • Let’s get back into this paradigm: sensory gating, maintaining and manipulating WM contents, and relaying motor commands.
  • How does adenosine control neuronal dysfunction and neurodegeneration? (Cunha 2016) (aaand it’s 77 pages of manuscript)
    • A2AR switch off A1R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the ‘activated’ synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change.
    • A1R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near-threshold and/or of short-duration, A1R trigger preconditioning, which may limit the spread of damage. Brain insults also up-regulate A2AR, probably to bolster adaptive changes, but this heightens brain damage since A2AR blockade affords neuroprotection in models of epilepsy, depression, Alzheimer’s, or Parkinson’s disease
  • There is also evidence, from a double-blind controlled trial in previously caffeine-naïve human volunteers, that acute caffeine can impact memory consolidation according to an Inverted-U function: Post-study caffeine administration enhances memory consolidation in humans
    • Pretty sure I heard fucking Huberman talk about this. Go figure it was published in Nature, his favorite. (In 2014)
  • Influences mental tracking: ADORA2A genotype modulates interoceptive and exteroceptive processing in a fronto-insular network (rs5751876) (no result for me)
    • The first thing to ask is if this is ‘moar A2A’, or less. Not sure. They do consume less caffeine, probably because of heightened sensitivity. So more??
    • TC was previously shown to be related to anxiety-related phenotypes.
    • TT risk genotype was associated with increased connectivity between the insula and the prefrontal cortex. The strength in connectivity correlated with interoceptive accuracy.
    • Carriers of the TT risk genotype furthermore displayed a reduced activity or deactivation in the striatum during executive control and decreased insula-striatal connectivity during the resting-state.
  • Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain

• All in all, blocking A2A is both anti- and pro-inflammatory. Istradefylline, an adenosine A2a receptor antagonist, inhibits the CD4+ T-cell hypersecretion of IL-17A and IL-8 in humans
• Istradefylline, an adenosine A2a receptor antagonist, ameliorates neutrophilic airway inflammation and psoriasis in mice
• Selective adenosine A2a receptor antagonism reduces JNK activation in oligodendrocytes after cerebral ischaemia

Supplementation #

• Everychem - $30 for 750mg
• Dose: 10m intranasal?
• 64-69 hour half life!