Isorhynchophylline

Isorhynchophylline at a Glance

Isorhynchophylline is a tetracyclic oxindole alkaloid of the Chinese Uncaria — chiefly U. rhynchophylla, the hooked vine known in Chinese medicine as gou teng — and is also present in Amazonian cat’s claw (U. tomentosa). It is the C7 stereoisomer (epimer) of rhynchophylline, differing only in the configuration at the spiro-centre, and the two are routinely isolated and studied together as gou teng’s marker oxindoles.

Where rhynchophylline leads with cardiovascular data, isorhynchophylline carries the marquee neuroprotective signal of the pair. Its distinctive thread is autophagy induction — it drives the autophagy-lysosome machinery that clears aggregation-prone proteins such as α-synuclein and amyloid-β — layered on top of the shared class actions: non-competitive NMDA-receptor antagonism and L-type calcium-channel-blocking vasodilation ^{1,2Reference 1Kang TH et al. · 2002Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytesView study →Reference 2Zhang WB et al. · 2004In vitroIn vitro vasodilator mechanisms of the indole alkaloids rhynchophylline and isorhynchophylline, isolated from the hook of Uncaria rhynchophylla (Miquel)View study →}. This is the most in-vivo-supported of the Uncaria oxindoles, with oral efficacy shown in Alzheimer’s-model rodents.

Two honest caveats frame everything below. First, all of it is preclinical — cell culture and rodents; there is no human trial of the isolate. Second, although isorhynchophylline is a shared Uncaria/Mitragyna alkaloid, it is only a minor and highly variable component of kratom — the pharmacology was worked out in Uncaria, and reading it onto a cup of kratom is not supported. A third, molecule-specific wrinkle matters too: isorhynchophylline has poor oral bioavailability and interconverts to rhynchophylline in the body, so some of its in-vivo neuro-benefit is likely delivered as its epimer ^{3,4Reference 3Wang X et al. · 2017AnimalDifferences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in ratsView study →Reference 4Zhang C et al. · 2019AnimalEvidence on integrating pharmacokinetics to find truly therapeutic agent for Alzheimer’s disease: comparative pharmacokinetics and disposition kinetics profiles of stereoisomers isorhynchophylline and rhynchophylline in ratsView study →}.

Isorhynchophylline vs. Rhynchophylline

Isorhynchophylline and rhynchophylline are C7 epimers — the same tetracyclic spiro-oxindole skeleton, differing only in the three-dimensional configuration at a single carbon. That near-identity is the defining fact of this molecule, and it cuts three ways.

• They interconvert. The two epimers equilibrate under heat during extraction and, more importantly, in vivo: after oral dosing of either epimer in rats, rhynchophylline is consistently the major/predominant form recovered in blood, brain and CSF ^{4Reference 4Zhang C et al. · 2019AnimalEvidence on integrating pharmacokinetics to find truly therapeutic agent for Alzheimer’s disease: comparative pharmacokinetics and disposition kinetics profiles of stereoisomers isorhynchophylline and rhynchophylline in ratsView study →}. Reading a “pure isorhynchophylline” animal result at face value is therefore risky — the exposed molecule is partly its sibling.
• Their pharmacology overlaps but is not identical. Both are non-competitive NMDA-receptor antagonists with near-matching potency (isorhynchophylline IC50 ≈ 48 µM vs rhynchophylline ≈ 43 µM) ^{1Reference 1Kang TH et al. · 2002Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytesView study →}, and both block L-type calcium channels to relax blood vessels — though rhynchophylline is somewhat more potent at inhibiting intracellular-store (caffeine/CPA-sensitive) calcium release at high concentrations ^{2Reference 2Zhang WB et al. · 2004In vitroIn vitro vasodilator mechanisms of the indole alkaloids rhynchophylline and isorhynchophylline, isolated from the hook of Uncaria rhynchophylla (Miquel)View study →}. Where isorhynchophylline pulls ahead is the autophagy / protein-clearance signal (below).
• Their pharmacokinetics diverge sharply. Isorhynchophylline is eliminated faster and has far lower systemic and brain exposure than rhynchophylline — oral bioavailability ~4% vs ~23% in rats ^{3Reference 3Wang X et al. · 2017AnimalDifferences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in ratsView study →} — which is why a comparative-PK study argued rhynchophylline may be the more “druggable” of the pair for the brain ^{4Reference 4Zhang C et al. · 2019AnimalEvidence on integrating pharmacokinetics to find truly therapeutic agent for Alzheimer’s disease: comparative pharmacokinetics and disposition kinetics profiles of stereoisomers isorhynchophylline and rhynchophylline in ratsView study →}.

Structurally, both sit in the tetracyclic oxindole family, distinct from Uncaria’s other alkaloid lines: the pentacyclic oxindole mitraphylline (an anti-inflammatory marker of cat’s claw) and the corynanthe indole hirsutine (the calcium-channel-blocking, antiviral alkaloid). And it should not be confused with kratom’s mitragynine: mitragynine is a corynanthe-indole µ-opioid partial agonist — a different scaffold with a different receptor — whereas isorhynchophylline is an oxindole with no opioid activity. The molecules co-occur in the Rubiaceae but are not pharmacological substitutes.

Neuroprotection & Autophagy

This is the section that makes isorhynchophylline its own page rather than a footnote to rhynchophylline. Beyond the shared NMDA antagonism, isorhynchophylline has a distinctive protein-clearance mechanism and the most convincing in-vivo anti-Alzheimer dataset of the Uncaria oxindoles.

Autophagy induction and aggregate clearance. In a landmark 2011/2012 Autophagy study, isorhynchophylline induced autophagy across several neuronal backgrounds (N2a, SH-SY5Y and PC12 lines plus primary cortical neurons) and, through the autophagy-lysosome pathway, promoted the degradation of α-synuclein — clearing wild-type, A53T and A30P monomers, α-synuclein oligomers and α-synuclein/synphilin-1 aggresomes ^{5Reference 5Lu JH et al. · 2012Isorhynchophylline, a natural alkaloid, promotes the degradation of α-synuclein in neuronal cells via inducing autophagyView study →}. Because α-synuclein accumulation is central to Parkinson’s disease and related synucleinopathies, this is a genuine, mechanistically-specific anti-aggregation / Parkinson lead — not merely a generic antioxidant claim.

Anti-amyloid, anti-tau neuroprotection. The compound’s Alzheimer’s-facing evidence climbs the usual ladder from cells to living animals:

• In PC12 cells, isorhynchophylline blunted amyloid-β toxicity, cutting Aβ-induced cell death, intracellular calcium overload and tau hyperphosphorylation ^{6Reference 6Xian YF et al. · 2012Bioassay-guided isolation of neuroprotective compounds from Uncaria rhynchophylla against beta-amyloid-induced neurotoxicityView study →}, with a follow-up study attributing the anti-apoptotic effect to PI3K/Akt (and CREB) signalling ^{7Reference 7Xian YF et al. · 2013Isorhynchophylline protects PC12 cells against beta-amyloid-induced apoptosis via PI3K/Akt signaling pathwayView study →}.
• In amyloid-β 25-35-injected rats, oral isorhynchophylline (20–40 mg/kg, 21 days) improved spatial memory, reduced hippocampal neuronal apoptosis (normalising Bcl-2/Bax, cleaved caspase-3/-9) and suppressed tau hyperphosphorylation at Ser396/Ser404/Thr205 via GSK-3β inhibition and PI3K/Akt activation ^{8Reference 8Xian YF et al. · 2014AnimalIsorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylationView study →}.
• Most tellingly, in the TgCRND8 transgenic mouse model of Alzheimer’s disease, four months of oral isorhynchophylline (40 mg/kg) ameliorated cognitive deficits while lowering cerebral amyloid-β and plaque load, tau hyperphosphorylation and neuroinflammation ^{9Reference 9Li HQ et al. · 2019AnimalIsorhynchophylline ameliorates cognitive impairment via modulating amyloid pathology, tau hyperphosphorylation and neuroinflammation: studies in a transgenic mouse model of Alzheimer’s diseaseView study →} — a rare instance of a Uncaria oxindole showing chronic oral efficacy in a genetic disease model.

NMDA antagonism and anti-addiction. The shared non-competitive NMDA-receptor antagonism ^{1Reference 1Kang TH et al. · 2002Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytesView study →} underwrites both excitotoxicity protection — isorhynchophylline (with rhynchophylline) protected hippocampal tissue against in-vitro ischemia-induced neuronal damage ^{10Reference 10Kang TH et al. · 2004In vitroProtective effect of rhynchophylline and isorhynchophylline on in vitro ischemia-induced neuronal damage in the hippocampus: putative neurotransmitter receptors involved in their actionView study →} — and an anti-addiction thread: isorhynchophylline ameliorated morphine dependence behaviours in zebrafish, an effect shown to depend on the microbiota-gut-brain axis (it reversed morphine-induced shifts in gut flora, and antibiotics abolished the benefit) ^{11Reference 11Chen Z et al. · 2021The ameliorative effects of isorhynchophylline on morphine dependence are mediated through the microbiota-gut-brain axisView study →}.

The honest reading: this is a coherent, multi-model neuro story with real in-vivo depth, but it remains entirely preclinical, and the epimer/PK caveat lingers — because isorhynchophylline interconverts to rhynchophylline and has low brain exposure ^{3,4Reference 3Wang X et al. · 2017AnimalDifferences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in ratsView study →Reference 4Zhang C et al. · 2019AnimalEvidence on integrating pharmacokinetics to find truly therapeutic agent for Alzheimer’s disease: comparative pharmacokinetics and disposition kinetics profiles of stereoisomers isorhynchophylline and rhynchophylline in ratsView study →}, the whole-animal benefits are partly a genus/epimer-pair effect rather than proof of a unique isorhynchophylline drug.

What It's Used For

Isorhynchophylline’s literature is neuro-forward and mechanistically specific — an autophagy-inducing, NMDA-antagonist neuroprotectant that also blocks L-type calcium channels — but entirely preclinical.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. No human isolate data, so scores stay low by design; the neuroprotective row edges up only because it has genuine chronic oral in-vivo (rat + transgenic-mouse) support.

01Neuroprotective (Anti-Alzheimer)Shaky40%Oral efficacy in Aβ rats + TgCRND8 AD mice; NMDA + PI3K/Akt/GSK-3β ^{1,8,9Reference 1Kang TH et al. · 2002Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytesView study →Reference 8Xian YF et al. · 2014AnimalIsorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylationView study →Reference 9Li HQ et al. · 2019AnimalIsorhynchophylline ameliorates cognitive impairment via modulating amyloid pathology, tau hyperphosphorylation and neuroinflammation: studies in a transgenic mouse model of Alzheimer’s diseaseView study →}

02Autophagy & Protein ClearanceShaky30%Autophagy-lysosome degradation of α-synuclein + Aβ aggregates ^{5,6Reference 5Lu JH et al. · 2012Isorhynchophylline, a natural alkaloid, promotes the degradation of α-synuclein in neuronal cells via inducing autophagyView study →Reference 6Xian YF et al. · 2012Bioassay-guided isolation of neuroprotective compounds from Uncaria rhynchophylla against beta-amyloid-induced neurotoxicityView study →}

03CardiovascularShaky28%L-type Ca²⁺-block vasodilation in isolated vessels + antihypertensive review ^{2,12Reference 2Zhang WB et al. · 2004In vitroIn vitro vasodilator mechanisms of the indole alkaloids rhynchophylline and isorhynchophylline, isolated from the hook of Uncaria rhynchophylla (Miquel)View study →Reference 12Zhou JY · 2012Isorhynchophylline: a plant alkaloid with therapeutic potential for cardiovascular and central nervous system diseasesView study →}

04Anti-inflammatoryShaky20%LPS-microglia cytokine/MAPK–NF-κB suppression ^{13Reference 13Yuan D et al. · 2009AnimalAnti-inflammatory effects of rhynchophylline and isorhynchophylline in mouse N9 microglial cells and the molecular mechanismView study →}

05Anti-addictionShaky16%Morphine-dependence reversal via gut-brain axis (zebrafish) ^{11Reference 11Chen Z et al. · 2021The ameliorative effects of isorhynchophylline on morphine dependence are mediated through the microbiota-gut-brain axisView study →}

Mechanisms

The load-bearing distinction from rhynchophylline is the autophagy row: isorhynchophylline doesn’t only antagonise the Ca²⁺-permeable NMDA receptor, it switches on the cell’s protein-clearance machinery — the mechanism behind its α-synuclein and amyloid-β aggregate clearing.

Pharmacokinetics

Isorhynchophylline’s pharmacokinetics are characterized only in rodents, and they are the molecule’s biggest liability. Its oral bioavailability in rats is very low — about 4%, roughly six-fold below rhynchophylline’s ~23% — driven mainly by faster hepatic first-pass metabolism ^{3Reference 3Wang X et al. · 2017AnimalDifferences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in ratsView study →}. In rat liver microsomes it is cleared ~1.9-fold faster than rhynchophylline (degradation half-life ~4.7-fold shorter), with CYP3A the predominant metabolising isoform and oxidation at the C-ring the major route ^{14Reference 14Wang X et al. · 2018In vitroStereoselective in vitro metabolism of rhynchophylline and isorhynchophylline epimers of Uncaria rhynchophylla in rat liver microsomesView study →}. Critically, the two epimers interconvert in vivo, and after oral dosing of either one rhynchophylline is the predominant form in blood, brain and CSF, with isorhynchophylline showing markedly lower brain and CSF disposition ^{4Reference 4Zhang C et al. · 2019AnimalEvidence on integrating pharmacokinetics to find truly therapeutic agent for Alzheimer’s disease: comparative pharmacokinetics and disposition kinetics profiles of stereoisomers isorhynchophylline and rhynchophylline in ratsView study →} — so systemic isorhynchophylline exposure is both small and partly re-badged as its sibling. There is no validated human pharmacokinetic data.

Clinical Trials

There are no human trials of isolated isorhynchophylline. All neuroprotective, autophagy, cardiovascular, anti-inflammatory and anti-addiction data are in-vitro or animal; human Uncaria/gou teng use is traditional and extract-based, not attributable to this single molecule.

Last checked: July 2026.

Isolate vs. Plant Studies

The evidence here is unusually isolate-forward for a botanical alkaloid, and — unlike most Uncaria molecules — it reaches whole living animals. Isorhynchophylline has been purified and tested directly in oocytes, neurons, microglia and isolated vessels ^{1,2,13Reference 1Kang TH et al. · 2002Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytesView study →Reference 2Zhang WB et al. · 2004In vitroIn vitro vasodilator mechanisms of the indole alkaloids rhynchophylline and isorhynchophylline, isolated from the hook of Uncaria rhynchophylla (Miquel)View study →Reference 13Yuan D et al. · 2009AnimalAnti-inflammatory effects of rhynchophylline and isorhynchophylline in mouse N9 microglial cells and the molecular mechanismView study →}, and, most importantly, dosed orally in intact rodents: Aβ-lesioned rats and TgCRND8 Alzheimer’s mice both improved on the pure compound ^{8,9Reference 8Xian YF et al. · 2014AnimalIsorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylationView study →Reference 9Li HQ et al. · 2019AnimalIsorhynchophylline ameliorates cognitive impairment via modulating amyloid pathology, tau hyperphosphorylation and neuroinflammation: studies in a transgenic mouse model of Alzheimer’s diseaseView study →}. That in-vivo depth is a real strength relative to siblings like mitraphylline or hirsutine, whose data are largely cell-level.

What is missing is the top of the ladder — there is no human dosed study of the isolate, and gou teng’s actual human use is as a whole hook/extract where isorhynchophylline co-acts with rhynchophylline, corynoxeine, hirsutine and geissoschizine methyl ether ^{15Reference 15Heitzman ME et al. · 2005Ethnobotany, phytochemistry and pharmacology of Uncaria (Rubiaceae)View study →}. Two isolate-specific caveats also blunt the “pure isorhynchophylline” reading: the compound’s low oral bioavailability ^{3Reference 3Wang X et al. · 2017AnimalDifferences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in ratsView study →} and its in-vivo interconversion to rhynchophylline ^{4Reference 4Zhang C et al. · 2019AnimalEvidence on integrating pharmacokinetics to find truly therapeutic agent for Alzheimer’s disease: comparative pharmacokinetics and disposition kinetics profiles of stereoisomers isorhynchophylline and rhynchophylline in ratsView study →} mean the animal benefits cannot be cleanly assigned to isorhynchophylline alone — they are, in part, an epimer-pair effect.

Prevalence in Nature

Isorhynchophylline is a hook/stem alkaloid of the genus Uncaria (Rubiaceae). Its richest and best-studied source is the Chinese gou teng, Uncaria rhynchophylla — the hooked branchlets used in Chinese medicine — where it and rhynchophylline are the marker tetracyclic oxindoles, co-occurring as an interconverting epimer pair; it also occurs in U. sinensis, U. macrophylla and Amazonian cat’s claw (U. tomentosa) ^{15Reference 15Heitzman ME et al. · 2005Ethnobotany, phytochemistry and pharmacology of Uncaria (Rubiaceae)View study →}. Total oxindole-alkaloid content in Uncaria is low — on the order of tenths of a percent of dry material — and varies widely with species, plant part, chemotype and season, which (together with heat-driven epimerisation during processing) makes any single “isorhynchophylline percentage” unstable ^{15Reference 15Heitzman ME et al. · 2005Ethnobotany, phytochemistry and pharmacology of Uncaria (Rubiaceae)View study →}.

Beyond Uncaria, isorhynchophylline is one of several oxindole alkaloids shared with kratom (Mitragyna speciosa), but there it is a minor and highly variable constituent, not a defining one — kratom’s pharmacology is driven by mitragynine and 7-hydroxymitragynine, not the oxindoles ^{16Reference 16Sengnon N et al. · 2023Seasonal and geographic variation in alkaloid content of kratom (Mitragyna speciosa (Korth.) Havil.) from ThailandView study →}. Clean quantitative per-source figures for the free alkaloid are sparse in the accessible literature; the specific ranges are logged as a gap to chase rather than guessed at here.

Discovery & Synthesis

Isorhynchophylline was isolated from Uncaria rhynchophylla by mid-20th-century natural-product chemists working on the traditional Chinese “gou teng” hook, and it is named as the iso- (C7-epimeric) form of rhynchophylline, with which it is always found. The exact first-isolation date and worker are not cleanly documented in the accessible literature. Its structure is a spiro-oxindole with a tetracyclic ring system that exists in heat-driven equilibrium with rhynchophylline, the two epimers interconverting during extraction and processing — a fact that complicates both isolation and any “single-alkaloid” quantitation ^{1,15Reference 1Kang TH et al. · 2002Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytesView study →Reference 15Heitzman ME et al. · 2005Ethnobotany, phytochemistry and pharmacology of Uncaria (Rubiaceae)View study →}.

Because Uncaria alkaloids are structurally intricate spiro-oxindoles present at low natural abundance, practical supply is still overwhelmingly by extraction from gou teng, and isorhynchophylline functions in practice as a standardization/quality marker for the herb rather than a manufactured drug substance. A first total synthesis and a modern preparative route are not well documented here.

Patents: not yet researched.

Toxicity & Safety

Isorhynchophylline carries a low flag on the available preclinical data — no LD50 or dedicated toxicology package for the isolate was located, and its active concentrations sit in the µM range. As with its epimer rhynchophylline, the honest qualifier is pharmacology, not documented harm: isorhynchophylline is genuinely cardioactive (an L-type calcium-channel blocker with review-level antiarrhythmic/bradycardic activity) and centrally active (non-competitive NMDA antagonism), so its plausible risks follow from those mechanisms. Its very low oral bioavailability ^{3Reference 3Wang X et al. · 2017AnimalDifferences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in ratsView study →} further limits systemic exposure from any oral route.

Safety at a Glance

✅ Low / no toxicityCardiac cautionDrug interactions

• Not mitragynine, not an opioid. A distinct oxindole scaffold; kratom’s opioid and dependence pharmacology does not apply.
• Cardioactive at pharmacological exposures. As an L-type Ca²⁺-channel blocker it is plausibly hypotensive/bradycardic and antiarrhythmic — the same properties that make it interesting make it something to respect.
• Additive with cardiovascular drugs. Plausibly additive with calcium-channel blockers, antihypertensives and antiarrhythmics.
• Central activity. Non-competitive NMDA antagonism means additive CNS effects are conceivable with sedatives and other NMDA-active agents.
• No human safety data or LD50. No genotoxicity or repeat-dose toxicology for the isolate was located; cardioactivity and CNS activity are inferred pharmacology, not measured harm.

Full Safety & Interactions Detail

Isorhynchophylline has a low verdict on the available preclinical data — no LD50, genotoxicity or repeat-dose study for the isolate was located, and its documented activity (vasodilation, NMDA antagonism, autophagy induction, microglial anti-inflammation) sits at µM concentrations ^{1,2,5,13Reference 1Kang TH et al. · 2002Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytesView study →Reference 2Zhang WB et al. · 2004In vitroIn vitro vasodilator mechanisms of the indole alkaloids rhynchophylline and isorhynchophylline, isolated from the hook of Uncaria rhynchophylla (Miquel)View study →Reference 5Lu JH et al. · 2012Isorhynchophylline, a natural alkaloid, promotes the degradation of α-synuclein in neuronal cells via inducing autophagyView study →Reference 13Yuan D et al. · 2009AnimalAnti-inflammatory effects of rhynchophylline and isorhynchophylline in mouse N9 microglial cells and the molecular mechanismView study →}.

The load-bearing caution is pharmacology, not toxicity signal: it is a genuine L-type calcium-channel blocker described with antiarrhythmic/bradycardic and central (NMDA-antagonist) activity in the review literature ^{12Reference 12Zhou JY · 2012Isorhynchophylline: a plant alkaloid with therapeutic potential for cardiovascular and central nervous system diseasesView study →}, so at pharmacological exposures the plausible risks are hypotension, bradycardia and conduction effects, with additive interaction with calcium-channel blockers, antihypertensives and antiarrhythmics, and additive CNS effects with sedatives. Its predominant metabolising enzyme is CYP3A ^{14Reference 14Wang X et al. · 2018In vitroStereoselective in vitro metabolism of rhynchophylline and isorhynchophylline epimers of Uncaria rhynchophylla in rat liver microsomesView study →}, the theoretical basis for any CYP3A-mediated interaction. It is chemically and pharmacologically distinct from kratom’s mitragynine: it has no opioid activity, and kratom’s dependence/respiratory profile must not be attributed to it.

Reproductive note (prose only). No dedicated reproductive-toxicity dataset exists for isolated isorhynchophylline, and Uncaria species are traditionally cautioned in pregnancy; pregnancy/lactation decisions belong on the herb or product page where intake is decided, not on this molecule page.

Dosage

There is no established human dose for isolated isorhynchophylline, and it is not a standalone supplement — it functions as a standardization marker for gou teng (Uncaria rhynchophylla) extracts, not a dosed ingredient. The evidence exists only as in-vitro concentrations (µM-range vasodilation and NMDA antagonism; ~48 µM NMDA IC50) ^{1Reference 1Kang TH et al. · 2002Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytesView study →} and animal doses (oral rodent 20–40 mg/kg neuroprotection studies) ^{8,9Reference 8Xian YF et al. · 2014AnimalIsorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylationView study →Reference 9Li HQ et al. · 2019AnimalIsorhynchophylline ameliorates cognitive impairment via modulating amyloid pathology, tau hyperphosphorylation and neuroinflammation: studies in a transgenic mouse model of Alzheimer’s diseaseView study →} — none of which is an oral human recommendation, and the compound’s ~4% oral bioavailability in rats ^{3Reference 3Wang X et al. · 2017AnimalDifferences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in ratsView study →} means even those animal doses translate poorly to systemic exposure. These are concentrations and doses studied in research and are not a personal recommendation.

References

1. Kang TH, Murakami Y, Matsumoto K, Takayama H, Kitajima M, Aimi N, Watanabe H (2002). Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytes. European Journal of Pharmacology. https://pubmed.ncbi.nlm.nih.gov/12433591/
2. Zhang WB, Chen CX, Sim SM, Kwan CY (2004). In vitro vasodilator mechanisms of the indole alkaloids rhynchophylline and isorhynchophylline, isolated from the hook of Uncaria rhynchophylla (Miquel). Naunyn-Schmiedeberg’s Archives of Pharmacology. https://pubmed.ncbi.nlm.nih.gov/14668978/
3. Wang X, Zheng M, Liu J, Huang Z, Bai Y, Ren Z, Wang Z, Tian Y, Qiao Z, Liu W, Feng F (2017). Differences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in rats. Journal of Ethnopharmacology. https://pubmed.ncbi.nlm.nih.gov/28755970/
4. Zhang C, Wu X, Xian Y, Zhu L, Lin G, Lin ZX (2019). Evidence on integrating pharmacokinetics to find truly therapeutic agent for Alzheimer’s disease: comparative pharmacokinetics and disposition kinetics profiles of stereoisomers isorhynchophylline and rhynchophylline in rats. Evidence-Based Complementary and Alternative Medicine. https://pubmed.ncbi.nlm.nih.gov/30854007/
5. Lu JH, Tan JQ, Durairajan SS, Liu LF, Zhang ZH, Ma L, Shen HM, Chan HY, Li M (2012). Isorhynchophylline, a natural alkaloid, promotes the degradation of α-synuclein in neuronal cells via inducing autophagy. Autophagy. https://pubmed.ncbi.nlm.nih.gov/22113202/
6. Xian YF, Lin ZX, Mao QQ, Hu Z, Zhao M, Che CT, Ip SP (2012). Bioassay-guided isolation of neuroprotective compounds from Uncaria rhynchophylla against beta-amyloid-induced neurotoxicity. Evidence-Based Complementary and Alternative Medicine. https://pubmed.ncbi.nlm.nih.gov/22778778/
7. Xian YF, Lin ZX, Mao QQ, Chen JN, Su ZR, Lai XP, Ip SP (2013). Isorhynchophylline protects PC12 cells against beta-amyloid-induced apoptosis via PI3K/Akt signaling pathway. Evidence-Based Complementary and Alternative Medicine. https://pubmed.ncbi.nlm.nih.gov/24319473/
8. Xian YF, Mao QQ, Wu JCY, Su ZR, Chen JN, Lai XP, Ip SP, Lin ZX (2014). Isorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation. Journal of Alzheimer’s Disease. https://pubmed.ncbi.nlm.nih.gov/24164737/
9. Li HQ, Ip SP, Yuan QJ, Zheng GQ, Tsim KKW, Dong TTX, Lin G, Han Y, Liu Y, Xian YF, Lin ZX (2019). Isorhynchophylline ameliorates cognitive impairment via modulating amyloid pathology, tau hyperphosphorylation and neuroinflammation: studies in a transgenic mouse model of Alzheimer’s disease. Brain, Behavior, and Immunity. https://pubmed.ncbi.nlm.nih.gov/31476414/
10. Kang TH, Murakami Y, Takayama H, Kitajima M, Aimi N, Watanabe H, Matsumoto K (2004). Protective effect of rhynchophylline and isorhynchophylline on in vitro ischemia-induced neuronal damage in the hippocampus: putative neurotransmitter receptors involved in their action. Life Sciences. https://pubmed.ncbi.nlm.nih.gov/15531384/
11. Chen Z, Chen Z, Zhou Y, Li C, Xiao S, Zhou Q, Ou J, Li J, Luo C, Mo Z (2021). The ameliorative effects of isorhynchophylline on morphine dependence are mediated through the microbiota-gut-brain axis. Frontiers in Pharmacology. https://pubmed.ncbi.nlm.nih.gov/34168553/
12. Zhou JY, Zhou SW (2012). Isorhynchophylline: a plant alkaloid with therapeutic potential for cardiovascular and central nervous system diseases. Fitoterapia. https://pubmed.ncbi.nlm.nih.gov/22406453/
13. Yuan D, Ma B, Yang JY, Xie YY, Wang L, Zhang LJ, Kano Y, Wu CF (2009). Anti-inflammatory effects of rhynchophylline and isorhynchophylline in mouse N9 microglial cells and the molecular mechanism. International Immunopharmacology. https://pubmed.ncbi.nlm.nih.gov/19781666/
14. Wang X, Qiao Z, Liu J, Zheng M, Liu W, Wu C (2018). Stereoselective in vitro metabolism of rhynchophylline and isorhynchophylline epimers of Uncaria rhynchophylla in rat liver microsomes. Xenobiotica. https://pubmed.ncbi.nlm.nih.gov/28990840/
15. Heitzman ME, Neto CC, Winiarz E, Vaisberg AJ, Hammond GB (2005). Ethnobotany, phytochemistry and pharmacology of Uncaria (Rubiaceae). Phytochemistry. https://pubmed.ncbi.nlm.nih.gov/15649507/
16. Sengnon N, Vonghirundecha P, Chaichan W, Juengwatanatrakul T, Onthong J, Kitprasong P, Sriwiriyajan S, Chittrakarn S, Limsuwanchote S, Wungsintaweekul J (2023). Seasonal and geographic variation in alkaloid content of kratom (Mitragyna speciosa (Korth.) Havil.) from Thailand. Plants (Basel). https://pubmed.ncbi.nlm.nih.gov/36840297/

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