Neuroprotective

Carnosic acid as it exists in the leaf is not electrophilic; its catechol becomes an electrophilic quinone on oxidation, so it behaves as a pro-electrophilic drug, largely inert in healthy tissue and converted to its active Keap1-alkylating form preferentially where oxidative stress already exists ^{8Reference 8Satoh T et al. · 2013ReviewNrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs — reviewView study →}.

Satoh’s group demonstrated the full chain: S-alkylation of specific Keap1 cysteines, Nrf2 activation, protection of cerebrocortical neurons against oxidative stress and excitotoxicity, translocation into brain, raised brain glutathione, and protection against middle-cerebral-artery ischaemia-reperfusion ^{9Reference 9Satoh T et al. · 2008In vitroCarnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1 — miceView study →}.

It also protects against 6-hydroxydopamine neurotoxicity in cell and rat Parkinson’s models by inducing antioxidant enzymes ^{10Reference 10Wu CR et al. · 2015In vitroCarnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro models of Parkinson’s disease — ratsView study →}, and a nanocarrier-packaged formulation improved cognition and reduced glia-mediated neuroinflammation in an Alzheimer’s model by disrupting a C/EBPβ-NF-κB interaction ^{11Reference 11Yi-Bin W et al. · 2022AnimalInhibition of the C/EBPβ–NF-κB interaction by nanocarrier-packaged carnosic acid ameliorates glia-mediated neuroinflammation and improves cognitive function in an Alzheimer’s disease model — miceView study →}.

Reviews of rosemary’s nervous-system pharmacology put carnosic acid at the centre of the effect ^{12,13Reference 12Ghasemzadeh Rahbardar M · 2020ReviewTherapeutic effects of rosemary (Rosmarinus officinalis L.) and its active constituents on nervous system disorders — reviewView study →Reference 13Mirza FJ et al. · 2023ReviewNeuroprotective effects of carnosic acid: insight into its mechanisms of action — reviewView study →}.

The conditional-activation account is a mechanistic argument rather than a clinical one: there is no human neuroprotection data for the molecule, rosemary’s human cognitive literature is aroma and whole herb, and the Alzheimer’s result needed a nanocarrier to deliver it.

Rosemary carries it.

A systematic review and meta-analysis of 13 rodent cerebral-ischaemia studies found tanshinone IIA reduced infarct volume (MD −16.26, 95% CI −20.76 to −11.77), brain water content (MD −4.89) and neurological deficit scores (MD −1.19), lowered GFAP and HMGB1 (MD −0.69), inhibited brain NF-κB and raised brain SOD (MD +68.31) ^{58Reference 58Xie X et al. · 2023Meta-analysisThe protective effect of tanshinone IIA on cerebral ischemic injury in animal models — systematic review and meta-analysis of 13 studiesView study →}.

Direction is uniform across studies, and the mechanism, less inflammation, oxidative stress and apoptosis, matches the cardiac work.

The human ischaemic-stroke trials cited alongside it are tanshinone IIA sodium sulfonate injection added to standard care ^{59Reference 59Liu F et al. · 2025Meta-analysisEfficacy and safety of tanshinone IIA sodium sulfonate injection as adjunctive therapy for stroke — systematic review and meta-analysis of randomised controlled trialsView study →}, a different molecule by a different route, and the rodent work is mostly parenteral dosing of the isolate.

Blood-brain-barrier penetration of orally dosed tanshinone IIA in humans has not been demonstrated.

Dan shen carries it.

Carnosic acid rather than carnosol owns the rosemary neuroprotection and blood-brain-barrier literature, and carnosol’s record is a set of single-laboratory findings.

In MOG-induced experimental autoimmune encephalomyelitis, the standard mouse MS model, it reduced clinical severity, CNS infiltration and demyelination, inhibited Th17 differentiation and STAT3 phosphorylation, blocked NF-κB nuclear translocation and switched infiltrating macrophage and microglial phenotype, working in the chronic phase and on passive transfer ^{14Reference 14Li X et al. · 2018Carnosol modulates Th17 cell differentiation and microglial switch in experimental autoimmune encephalomyelitisView study →}.

A 2025 screen identified carnosol as an inhibitor of SARM1 NAD⁺-cleavage activity, the executioner of axon degeneration, with symptom improvement in a peripheral-neuropathy model ^{15Reference 15Murata H et al. · 2025Carnosol, a rosemary ingredient discovered in a screen for inhibitors of SARM1-NAD(+) cleavage activity, ameliorates symptoms of peripheral neuropathyView study →}.

Carnosol and carnosic acid also reduce PrP^Sc accumulation and disrupt formed prion aggregates in cell-free assays, independently of their antioxidant effects ^{16Reference 16Karagianni K et al. · 2022In vitroCarnosic acid and carnosol display antioxidant and anti-prion properties in in vitro and cell-free models of prion diseasesView study →}.

None of it has been replicated, and there is no data on whether carnosol reaches the human brain at dietary exposure.

Rosemary carries it.

Casuarinin prevented glutamate-induced apoptosis in HT22 hippocampal cells by suppressing intracellular ROS production and the MAPK activation it drives ^{17Reference 17Song JH et al. · 2017Protective effect of casuarinin against glutamate-induced apoptosis in HT22 cells through inhibition of oxidative stress-mediated MAPK phosphorylationView study →}, and showed dose-dependent anti-neuroinflammatory activity in microglia with protection of neuroblastoma cells ^{18Reference 18Perera HDSM et al. · 2025In vitroInvestigating the antioxidant, pro-inflammatory enzyme inhibitory, neuroprotective, and antineuroinflammatory bioactives of Osbeckia octandra using in vitro and in silico approachesView study →}.

A 936 Da polyphenol that does not cross the gut wall does not cross the blood-brain barrier, so the findings describe a mechanism in a dish.

The same limit applies to the cell-free acetylcholinesterase IC₅₀ of 34 ± 2 nM, marginally more potent than donepezil at 44 nM in the same assay ^{19Reference 19Orabi MAA et al. · 2023Structural determination and anticholinesterase assay of C-glycosidic ellagitannins from Lawsonia inermis leaves — a study supported by DFT calculations and molecular dockingView study →}, a single unreplicated cell-free result on a promiscuous protein binder.

Raspberry leaf and arjuna carry it.

In mice with transient middle cerebral artery occlusion, sodium danshensu given at 1, 3, 6 or 9 hours after occlusion established a therapeutic window of 6 hours, beyond which the effect vanished, a dose-timing experiment almost nothing else in the field has.

The mechanism is direct Nrf2 binding, confirmed by surface plasmon resonance, with ferroptosis markers corrected and protection partially abolished in Nrf2-deficient mice ^{20Reference 20Guo C et al. · 2025Therapeutic time window of sodium danshensu on cerebral ischemia and its mechanism of inhibiting oxidative stress and ferroptosis through the Nrf2 pathwayView study →}.

The wider neurological literature, cognitive impairment, Parkinson’s models, anxiety-like and antidepressant-type behaviour, has one or two studies each ^{21,22Reference 21Zhang J et al. · 2019Therapeutic potentials and mechanisms of the Chinese traditional medicine DanshensuView study →Reference 22Yang Y et al. · 2025Danshensu derivatives — a series of promising drugs with protective effects against cardiocerebrovascular diseases and cancersView study →}.

The Chinese injectables used clinically in stroke (Danhong, danshen depside salt, salvianolate) are mixtures in which danshensu is one quantified marker, and their outcomes belong to the preparations.

Danshensu is the catechol with the greatest systemic exposure in humans, rats and dogs after Danhong injection, while salvianolic acids A and B showed low plasma levels and their human metabolites were little or not detected ^{23Reference 23Li M et al. · 2015Clinical trialSystemic exposure to and disposition of catechols derived from Salvia miltiorrhiza roots (danshen) after intravenous dosing DanHong injection in human subjects, rats, and dogsView study →}.

Dan shen carries it.

Eburnamonine’s neuroprotection is an oxygen-delivery mechanism rather than a receptor one, and it is well specified because the molecule was developed as the drug vinburnine.

It raises red-cell 2,3-diphosphoglycerate and ATP, shifting the oxyhaemoglobin dissociation curve so haemoglobin releases oxygen more readily to tissue, shown in human volunteers after oral dosing ^{28Reference 28Linée P et al. · 1981Experimental approach of activity and mechanism(s) of action of drugs used in cerebral metabolic insufficiencyView study →}, in double-blind elderly-volunteer studies after a 100 mg infusion and on chronic oral treatment ^{29Reference 29Ferretti PG et al. · 1982Clinical trialEffects of acute and chronic treatment with (-)eburnamonine on the tissue supply of oxygen — clinical trialView study →}, and in normobaric hypoxic rats (+10% 2,3-DPG, +28% ATP at 21 days), where the authors attributed it to stimulated anaerobic glycolysis rather than a direct change in haemoglobin-oxygen affinity ^{30Reference 30Louajri A et al. · 1999AnimalRed blood cell metabolism and hemoglobin oxygen affinityView study →}.

Upstream, l-eburnamonine raised cerebral oxygen supply and consumption in anaesthetised dogs, protected rodents against hypoxia and slowed the fall in cerebral energy charge after hypoxia ^{31,32,28Reference 31Linée P et al. · 1978Cerebral metabolic, hemodynamic and antihypoxic properties of l-eburnamonineView study →Reference 32Villa RF et al. · 1978Effect of (-)eburnamonine, papaverine and UDP-glucose on cerebral energy state during and after experimental hypoxia and ischaemia in beagle dogView study →Reference 28Linée P et al. · 1981Experimental approach of activity and mechanism(s) of action of drugs used in cerebral metabolic insufficiencyView study →}.

These are biomarkers rather than outcomes: no study links the P50 shift to a clinical endpoint, and the one paper testing an ischaemic recovery endpoint, gerbil electrocortical recovery after 10 minutes of ischaemia, found vinburnine ineffective ^{33Reference 33Barzaghi F et al. · 1986A comparison of some of the pharmacological properties of the new eburnamenine derivative vindeburnol with those of vincamine, vinburnine, dihydroergotoxine mesilate and nicergolineView study →}.

Free-radical scavenging is not the mechanism, since it was inactive in an alloxan-cytotoxicity model ^{34Reference 34Bentué-Ferrer D et al. · 1989Comparative evaluation of scavenger properties of exifone, piracetam and vinburnineView study →}.

All of it is isolate data at 60 to 180 mg/day drug doses, with nothing whole-plant.

Lesser periwinkle carries it.

In rats given intravenous salvianolic acid A at reperfusion after transient middle cerebral artery occlusion, infarct area, brain water content and neurological deficit all fell, and plasma exposure was identical between stroke and sham animals while brain exposure was 9.17-fold higher in the stroke animals ^{43Reference 43Feng SQ et al. · 2017AnimalPharmacokinetic and metabolomic analyses of the neuroprotective effects of salvianolic acid A in a rat ischemic stroke modelView study →}.

The molecule concentrates where the blood-brain barrier is broken, and GC/MS metabolomics confirmed it corrected ischaemia-driven metabolic disturbance in brain tissue more than in serum ^{43Reference 43Feng SQ et al. · 2017AnimalPharmacokinetic and metabolomic analyses of the neuroprotective effects of salvianolic acid A in a rat ischemic stroke modelView study →}.

On the prevention side, oral Sal A (10 mg/kg twice daily for five days before an autologous-thrombus stroke) reduced intracerebral haemorrhage and barrier disruption, preserving ZO-1, occludin and claudin-5 and suppressing MMP upregulation through Src inhibition, the same Src node as its lung-injury work ^{44Reference 44Liu CD et al. · 2021Salvianolic acid A prevented cerebrovascular endothelial injury caused by acute ischemic stroke through inhibiting the Src signaling pathwayView study →}.

A 2024 review collates the post-stroke neuroinflammation literature and identifies the ischaemia-gated brain entry as the property that makes it a plausible stroke agent ^{45Reference 45Yang H et al. · 2024Targeting post-stroke neuroinflammation with salvianolic acid A — molecular mechanisms and preclinical evidenceView study →}.

The positive human findings that review mentions refer to salvianolic acids as a mixture, the approved Chinese injectable specified around salvianolic acid B, and not to Sal A ^{45Reference 45Yang H et al. · 2024Targeting post-stroke neuroinflammation with salvianolic acid A — molecular mechanisms and preclinical evidenceView study →}.

Dan shen carries it.

Salvianolic acid B appears across cerebral-ischaemia models in the danshen literature, CD40/NF-κB suppression with reduced platelet activation, Nrf2/HO-1-driven angiogenesis in stroke recovery, and TGF-β1/Smad3-mediated reduction of cerebral injury, in rodent and cell studies.

The human stroke evidence attaches to injectable compound preparations (salvianolate lyophilised injection, Salvia with ligustrazine injection, tanshinone IIA sodium sulfonate injection) rather than to Sal B. The 2023 review lists depression and spinal-cord injury among the protected conditions ^{46Reference 46He G et al. · 2023ReviewSalvianolic acid B — a review of pharmacological effects, safety, combination therapy, new dosage forms and novel drug delivery routesView study →}.

No molecular target is uniquely Sal B’s, the mechanism set is the shared antioxidant and anti-inflammatory one in brain tissue, and stroke-trial numbers from injectable mixtures do not attach to the molecule.

Dan shen carries it.

Group-level human data exists and is intravenous.

Salvianolic acids for injection (SAFI) plus conventional treatment across 14 RCTs and 1,309 patients with acute cerebral infarction improved the total effective rate (RR 1.35, 95% CI 1.25–1.44) and reduced NIHSS in a dose-separated way (130 mg: WMD −3.31; 100 mg: WMD −1.91), with improved activities of daily living, cognitive function, haemorheology and CRP and no serious adverse reactions, at low GRADE quality ^{47Reference 47Lyu J et al. · 2019Meta-analysisSalvianolic acids for injection combined with conventional treatment for patients with acute cerebral infarction — a systematic review and meta-analysis of randomized controlled trialsView study →}.

The mechanism review adds reduced neuroinflammation and oxidative stress, inhibited apoptosis, preserved endothelial function and blood-brain-barrier integrity, and promoted angiogenesis ^{48Reference 48Zhao C et al. · 2024The therapeutic effects of salvianolic acids on ischemic stroke — from molecular mechanisms to clinical applicationsView study →}.

Salvianolic acid A specifically has enhanced cerebral penetration after ischaemia, which makes it the family’s neurological candidate ^{45Reference 45Yang H et al. · 2024Targeting post-stroke neuroinflammation with salvianolic acid A — molecular mechanisms and preclinical evidenceView study →}.

No trial has tested any isolated salvianolic acid in stroke patients, and the human evidence is for the intravenous mixture in Chinese trials only.

Dan shen carries them.

Two distinct protective routes are documented.

In high-glucose neurons and streptozotocin-diabetic rats, sarsasapogenin suppresses BACE1-driven Aβ overproduction and AKT/GSK-3β-mediated tau hyperphosphorylation, and a PPARγ antagonist abolishes both effects, placing PPARγ activation upstream ^{49Reference 49Zhang YM et al. · 2021Sarsasapogenin attenuates Alzheimer-like encephalopathy in diabetesView study →}.

Separately, it binds and stabilises GPX4, confirmed by cellular thermal shift assay and surface plasmon resonance (K_D 44.6 µM), an anti-ferroptotic mechanism ^{50Reference 50Wang F et al. · 2025Sarsasapogenin stimulates angiogenesis and osteogenesis coupling to treat estrogen deficiency-induced osteoporosis by activating the GPX4/SLIT3/ROBO1 axisView study →}.

It also protects PC12 cells against Aβ42 and H₂O₂ cytotoxicity in vitro ^{51Reference 51Kashyap P et al. · 2020Sarsasapogenin: a steroidal saponin from Asparagus racemosus as multi target directed ligand in Alzheimer’s diseaseView study →}.

The GPX4 affinity is weak relative to any plausible plasma concentration from a herbal dose, and nothing has been tested in a human.

Sarsaparilla and shatavari carry it.

Both neuroprotection results use the isolated molecule and both run through its anti-inflammatory mechanism.

In an MPTP mouse model of Parkinson’s disease, tanshinone I improved rotarod motor function, normalised striatal neurotransmitters and protected nigrostriatal dopaminergic neurons, modulating microglial activation and attenuating the TNF-α rise; it did not alter MPP⁺ concentration, which rules out the confound of blocking toxin activation, and oral 10 mg/kg daily for two weeks produced no liver toxicity ^{56Reference 56Wang S et al. · 2015AnimalTanshinone I selectively suppresses pro-inflammatory genes expression in activated microglia and prevents nigrostriatal dopaminergic neurodegeneration in a mouse model of Parkinson’s diseaseView study →}.

In a gerbil transient global cerebral ischaemia model (5 minutes of occlusion), pre-treatment protected hippocampal CA1 pyramidal neurons from delayed death; IL-4 and IL-13 rose with treatment without a matching rise in IL-2 or TNF-α, cytokine levels were maintained after ischaemia rather than collapsing, and exogenous IL-4 alone did not protect ^{57Reference 57Park JH et al. · 2014Anti-inflammatory effect of tanshinone I in neuroprotection against cerebral ischemia-reperfusion injury in the gerbil hippocampusView study →}.

Each model has one study from one group, the ischaemia study uses pre-treatment rather than post-insult dosing, and no blood-brain-barrier penetration data exists for tanshinone I. Danshen’s clinical stroke literature tests water-type injectable preparations and does not support the molecule.

Dan shen carries it.

Long-term oral urolithin A improved learning, memory and olfactory function across three Alzheimer’s transgenic mouse models, reduced amyloid-β and tau pathology and enhanced long-term potentiation, through mitophagy induction achieved by restored lysosomal function, with normalisation of lysosomal cathepsins, cathepsin Z in particular, as the critical node ^{60Reference 60Hou Y et al. · 2024AnimalUrolithin A improves Alzheimer’s disease cognition and restores mitophagy and lysosomal functions — three transgenic mouse modelsView study →}.

That rests on the well-replicated finding that urolithin A activates mitophagy in C. elegans, rodents and human skeletal muscle ^{61,62,63Reference 61Ryu D et al. · 2016AnimalUrolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodentsView study →Reference 62Andreux PA et al. · 2019The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans — first-in-human, safety as primary outcomeView study →Reference 63Singh A et al. · 2022RCTUrolithin A improves muscle strength, exercise performance and biomarkers of mitochondrial health in a randomized trial in middle-aged adults (NCT03464500) — primary endpoint peak power output not metView study →}.

It is mouse-only, there is no human cognitive trial, and the dedicated PBPK model concluded that the concentrations at which neuroprotective effects have been observed in vitro appear unlikely to be achieved in vivo from supplementation ^{64Reference 64Aichinger G et al. · 2023Physiologically-based pharmacokinetic modeling of the postbiotic supplement urolithin A predicts its bioavailability is orders of magnitude lower than concentrations that induce toxicity, but also neuroprotective effectsView study →}.

It is a mechanistic hypothesis with strong animal support rather than a human finding.

In D-galactose-accelerated ageing mice, urolithin B improved learning and memory, inhibited cytochrome-c release from mitochondria, downregulated JNK signalling and activated ERK and PI3K/Akt with downstream p44/42 MAPK phosphorylation, shifting neurons toward survival rather than apoptosis ^{65Reference 65Chen P et al. · 2021AnimalThe gut microbiota metabolite urolithin B improves cognitive deficits by inhibiting Cyt C-mediated apoptosis and promoting the survival of neurons through the PI3K pathway in aging miceView study →}.

The neuroinflammatory arm is the microglial work, including suppression of microglial activation in LPS-injected mouse brain ^{66Reference 66Lee G et al. · 2019Anti-inflammatory and antioxidant mechanisms of urolithin B in activated microgliaView study →}.

Supporting in-vitro results include protection of PC12 cells against glutamate toxicity and attenuation of cerebral ischaemia-reperfusion injury through Nrf2 in rats.

There is no human data, and no study has demonstrated brain penetration of urolithin B or of its glucuronide, the form that circulates.

Beyond perfusion, isolated vincamine protects neurons directly in disease models through the Nrf2/HO-1 up, NF-κB down axis that runs through its organ-protection work: reduced dopaminergic neuron loss, neuroinflammation and oxidative damage in a mouse Parkinson’s model ^{67Reference 67Wang et al. · 2024AnimalVincamine alleviates brain injury by attenuating neuroinflammation and oxidative damage in a mouse model of Parkinson’s disease through NF-κB and Nrf2/HO-1 signalling — animal modelView study →}, retinal ganglion-cell protection in rat anterior ischaemic optic neuropathy ^{68Reference 68Li et al. · 2021AnimalEfficacy of vincamine treatment in a rat model of anterior ischaemic optic neuropathy — animal modelView study →}, and reduced amyloid-β-induced ROS and apoptosis in PC12 cells ^{69Reference 69Han et al. · 2017In vitroVincamine alleviates amyloid-β 25-35 peptide-induced cytotoxicity in PC12 cells — in vitroView study →}.

The novel target is GPR40 (FFAR1): in female 3×Tg-AD mice, vincamine acting as a GPR40 agonist suppressed neuroinflammation and tau hyperphosphorylation while improving synaptic plasticity ^{70Reference 70Lyu et al. · 2026AnimalVincamine as a GPR40 agonist shows potential in treating female Alzheimer’s disease — animal modelView study →}.

Brain access is not the constraint, since vincamine equilibrates rapidly between rat blood and hippocampus and shows minimal P-gp/BCRP efflux interaction ^{71,72Reference 71Juan et al. · 2005AnimalMeasurement and pharmacokinetics of vincamine in rat blood and brain using microdialysis — animal pharmacokineticsView study →Reference 72Fandy et al. · 2016In vitroIn vitro characterization of transport and metabolism of the alkaloids: vincamine, vinpocetine and eburnamonine — in vitroView study →}.

Every neuroprotection result is preclinical, and the GPR40 identity rests on a single overlapping research cluster ^{70,73,74Reference 70Lyu et al. · 2026AnimalVincamine as a GPR40 agonist shows potential in treating female Alzheimer’s disease — animal modelView study →Reference 73Xu et al. · 2023AnimalVincamine as an agonist of G-protein-coupled receptor 40 effectively ameliorates diabetic peripheral neuropathy in mice — animal modelView study →Reference 74Zhao et al. · 2023AnimalVincamine as an agonist of G protein-coupled receptor 40 effectively ameliorates pulmonary fibrosis in mice — animal modelView study →}.

Lesser periwinkle carries it.

Achillolide A’s pharmacological record is neuroprotection in cultured brain cells through the MAPK cascade.

In primary astrocytes it blocked H₂O₂-induced phosphorylation of MEK1 and p44/42 MAPK while lowering intracellular ROS, not by scavenging H₂O₂ directly, and in differentiated N2a neuroblastoma cells it did the same under glutamate and β-amyloid challenge, adding SAPK/JNK ^{1,2,3Reference 1Elmann A et al. · 2016In vitroAchillolide A protects astrocytes against oxidative stress by reducing intracellular reactive oxygen species and interfering with cell signaling — [in vitro]View study →Reference 2Elmann A et al. · 2017In vitroGlutamate toxicity to differentiated neuroblastoma N2a cells is prevented by the sesquiterpene lactone achillolide A and the flavonoid 3,5,4′-trihydroxy-6,7,3′-trimethoxyflavone from Achillea fragrantissima — [in vitro]View study →Reference 3Elmann A et al. · 2018In vitroElmann A, Telerman A, Ofir R, Kashman Y, Lazarov O (2018). β-amyloid cytotoxicity is prevented by natural achillolide A — [in vitro]. Journal of Natural Medicines. https://pubmed.ncbi.nlm.nih.gov/29546477/View study →}; in LPS-activated primary microglia it suppressed NO, iNOS, COX-2, MMP-9, IL-1β and TNF-α together ^{4Reference 4Elmann A et al. · 2015In vitroDownregulation of microglial activation by achillolide A — [in vitro]View study →}.

No target engagement has been shown, since these are downstream phosphorylation readouts rather than evidence of kinase binding.

The molecule carries an exocyclic α-methylene ketone, the alkylating motif that makes sesquiterpene lactones as a class hit NF-κB, Nrf2 and MAPK-adjacent signalling non-specifically ^{5,6Reference 5Siedle B et al. · 2004In vitroQuantitative structure-activity relationship of sesquiterpene lactones as inhibitors of the transcription factor NF-kappaB — [in vitro structure–activity study of 103 lactones]View study →Reference 6Wagner S et al. · 2006Development of a structural model for NF-kappaB inhibition of sesquiterpene lactones using self-organizing neural networksView study →}, and the control that would separate specific pharmacology from generalised cysteine alkylation has not been run.

The one in-vivo test, 25 µg i.p. daily for 28 days in APPswe/PS1ΔE9 mice, produced a statistically insignificant behavioural trend and no change in soluble or oligomeric Aβ ^{7Reference 7Bartolotti N et al. · 2018AnimalPhytochemicals from Achillea fragrantissima are modulators of AβPP metabolism — [mouse in vivo]View study →}.

There is no pharmacokinetic, oral-dosing or blood-brain-barrier data.

Achillea fragrantissima carries it.

A diffuse but consistently positive rodent signal runs across dissimilar models: NGF stimulation and improved spatial memory in an amyloid-β(1-42) rat model ^{24Reference 24Som S et al. · 2022AnimalNeuroprotective role of diosgenin, an NGF stimulator, against Aβ(1-42)-induced neurotoxicity in an animal model of Alzheimer’s disease — rat in vivo studyView study →}, Nrf2/HO-1-mediated nerve protection in diabetic peripheral neuropathy ^{25Reference 25Leng J et al. · 2020AnimalNeuroprotective effect of diosgenin in a mouse model of diabetic peripheral neuropathy involves the Nrf2/HO-1 pathway — mouse in vivo studyView study →}, and HSP70-mediated NF-κB suppression in cerebral ischaemia ^{26Reference 26Zhang X et al. · 2022AnimalDiosgenin revealed potential effect against cerebral ischemia reperfusion through the HIKESHI/HSP70/NF-κB anti-inflammatory axis — rat in vivo studyView study →}.

All of it is isolate work; brain exposure after oral dosing has not been characterised, and given the absorption profile ^{27Reference 27Manda VK et al. · 2013In vitroCharacterization of in vitro ADME properties of diosgenin and dioscin from Dioscorea villosa — in vitro studyView study →} the real-world contribution is small.

Wild yam and fenugreek carry it.

In rat cortical synaptosomes epigoitrin cut 4-aminopyridine-evoked glutamate release with an IC₅₀ of 3 µM; the effect disappeared without extracellular Ca²⁺ or with a P/Q-type channel blocker and survived N-type blockade, a specific presynaptic locus rather than a generic membrane effect ^{35Reference 35Chang Y et al. · 2025AnimalEpigoitrin decreases synaptosomal glutamate release and protects neurons from glutamate excitotoxicity in ratsView study →}.

In vivo, pretreatment before kainic acid reduced cortical neuronal injury, glutamate elevation and the excitotoxicity effectors DAPK1 and GluN2B, with lower ROS, less glial activation, lower TNF-α, IL-1β and IL-6 and higher IL-10 ^{35Reference 35Chang Y et al. · 2025AnimalEpigoitrin decreases synaptosomal glutamate release and protects neurons from glutamate excitotoxicity in ratsView study →}.

Exposure is the limit: no data shows oral epigoitrin reaching brain tissue at 3 µM, and a pharmacopoeia-compliant Ban Lan Gen dose delivers only about 1.8 to 3 mg of the two goitrins combined ^{36Reference 36Ngai HL et al. · 2025Quality assessment of medicinal material Daqingye and Banlangen from Isatis tinctoria Fort. reveals widespread substitution with Strobilanthes speciesView study →}.

One paper, one group, isolate in rats.

Isatis carries it.

Park (2009) reported that isorosmanol protected PC12 cells against β-amyloid-induced toxicity and separately promoted neurite generation, an effect enhanced by co-treatment with nerve growth factor, with F-actin redistribution and increased neurofilament expression, the cytoskeletal signature of differentiation rather than cell rounding ^{37Reference 37Park SY · 2009Neuroprotective and neurotrophic effects of isorosmanolView study →}.

It is a single short paper in a rat pheochromocytoma line used as a neuron surrogate, with no concentrations in the abstract, no replication in 17 years, no animal work and no identified mechanism, and PC12 neurite-outgrowth assays are permissive.

The acetylcholinesterase literature for isorosmanol is internally contradictory by roughly 500,000-fold: Sallam reports 65% inhibition at 500 µM ^{38Reference 38Sallam A et al. · 2016Acetylcholine esterase inhibitors and melanin synthesis inhibitors from Salvia officinalisView study →} while Köksal and Şenol report an IC₅₀ of 0.98 nM ^{39Reference 39Köksal Z · 2025In vitroAnticholinesterase and carbonic anhydrase inhibitory activities of natural carnosic acid derivatives: a comprehensive in vitro and in silico studyView study →} on a panel where two compounds return identical IC₅₀ values to three significant figures against four unrelated enzymes and the whole set beats tacrine 10 to 60 times.

The defensible figure is the weak one, and 500 µM is non-specific phenol behaviour, so no cholinergic mechanism attaches to the molecule.

Rosemary and sage carry it.

Two cell studies from one laboratory carry the molecule.

In C6 glial cells, scopolamine drove apoptosis through oxidative stress, caspase-3 activation and mitochondrial dysfunction while suppressing SOD, glutathione peroxidase, catalase and NRF2; lactucopicrin reversed each marker and restored NGF secretion and neurite outgrowth in N2a cells ^{40Reference 40Venkatesan R et al. · 2016In vitroLactucopicrin ameliorates oxidative stress mediated by scopolamine-induced neurotoxicity through activation of the NRF2 pathway — in vitroView study →}.

The follow-up showed neuritogenesis and raised NGF, BDNF and NT-3 through Ca²⁺/CaMKII/ATF1 ^{41Reference 41Venkatesan R et al. · 2017In vitroLactucopicrin potentiates neuritogenesis and neurotrophic effects by regulating Ca²⁺/CaMKII/ATF1 signaling pathway — in vitroView study →}.

NRF2 activation is the canonical response to any thiol-reactive electrophile ^{42Reference 42Schmidt TJ · 1999In vitroHelenanolide type sesquiterpene lactonesView study →}, so the antioxidant-enzyme arm is class behaviour rather than molecular identity; the CaMKII/ATF1 neurotrophic arm is the distinctive part, and it rests on one unreplicated paper.

Cell models only, a single group, and no blood-brain-barrier or exposure data.

Wild lettuce carries it.

The most complete in-vivo dataset on this molecule is in an invertebrate.

In C. elegans, shatavarin IV reduced α-synuclein aggregation and lipid accumulation and restored dopamine in a Parkinson’s model, up-regulating pdr-1, ubc-12 and pink-1 ^{52Reference 52Smita SS et al. · 2017AnimalShatavarin IV elicits lifespan extension and alleviates Parkinsonism in Caenorhabditis elegansView study →}; raised synaptic acetylcholine by inhibiting cholinesterase and up-regulating cha-1 and cho-1, with increased nicotinic-receptor activity through unc-38 and unc-50 ^{53Reference 53Shuchi Smita S et al. · 2021AnimalNeuromodulatory potential of Asparagus racemosus and its bioactive molecule Shatavarin IV by enhancing synaptic acetylcholine level and nAChR activityView study →}; and extended lifespan 18% through an eat-2/mTOR/PHA-4-dependent autophagy route requiring bec-1, unc-51 and lgg-1 ^{54Reference 54Smita SS et al. · 2020AnimalA bioactive compound Shatavarin IV-mediated longevity as revealed by dietary restriction-induced autophagy in Caenorhabditis elegansView study →}.

The mammalian counterpart is TrkB-BDNF cell work ^{55Reference 55Das D et al. · 2026In vitroShatavarin IV, a bioactive constituent of Asparagus racemosus, exerts antioxidant and anti-inflammatory effects in LPS-treated cultured SH-SY5Y cells via TrkB-BDNF axisView study →}.

Three of the four studies come from one laboratory, there is no rodent behavioural or neuropathological study, and an experimental piracetam/shatavarin IV nanoemulsion has been formulated specifically to get the molecule across the blood-brain barrier.

Shatavari carries it.