According to Gemini, Ibudilast is a “broad-spectrum” PDE inhibitor with a heavy focus on the central nervous system. It is superior if the primary goal is to prevent the physical shrinking of brain tissue. To reduce dementia risk, shall we consider Ibudilast over Tadalafil?
Interesting! Unfortunately it doesn’t seem like it’s sold in India (so no luck with the regular India-based online pharmacies). Seems hard to get, unless you know of some sources…
It is available from some Japanese online pharmacies. It is sold as the brand name “KETAS Capsules”. In the past, I had good experiences with some Japanese online pharmacies.
Alzheimer’s disease drug development has a notoriously high clinical failure rate, largely due to an industry-wide focus on clearing amyloid plaques rather than addressing the multifactorial nature of the disease, including chronic neuroinflammation. A recent preclinical study utilized a novel multi-scale predictive modeling framework—combining machine learning, biophysics, and systems pharmacology—to screen existing drugs against the molecular signatures of human Alzheimer’s patients. The framework identified Ibudilast (IBU), a drug already approved in Asia for asthma and stroke, as a high-potential candidate for repurposing.
IBU operates as a phosphodiesterase (PDE) inhibitor and a Toll-like receptor 4 (TLR4) antagonist. When administered daily over six months to a transgenic rat model exhibiting progressive, age-dependent Alzheimer’s pathology, the drug produced significant neuroprotective effects. Treated rats demonstrated marked improvements in spatial learning and memory, alongside a targeted reduction in amyloid plaque burden and tau paired-helical filaments, localized specifically within the dentate gyrus of the hippocampus. Furthermore, IBU significantly reduced the ratio of amoeboid-to-ramified microglia, shifting the brain’s resident immune cells away from a destructive, hyper-reactive state.
Notably, RNA sequencing of hippocampal tissue revealed that IBU modulates the TLR and ubiquitin-proteasome pathways in a strictly sex-dependent manner, highlighting an under-explored variable in Alzheimer’s pathology. While the drug successfully mitigated behavioral deficits and reduced physical protein aggregations, it did not rescue existing neuronal loss. This data indicates that IBU functions as a potent anti-inflammatory and disease-modifying agent, but lacks regenerative capabilities once neurons have died. The findings offer a compelling, actionable rationale for targeting neuroinflammation early in the disease progression to preserve cognitive function.
Context
Institution: City University of New York (CUNY), Hunter College, Weill Cornell Medicine.
Country: United States.
Journal Name: Brain. Impact Evaluation The impact score of this journal is 11.7, evaluated against a typical high-end range of 0–60+ for top general science, therefore this is a High impact journal.
Mechanistic Deep Dive
Neuroinflammation via TLR4: IBU functions as a TLR4 antagonist, suppressing the pro-inflammatory cascade. RNA sequencing indicates IBU inhibits IRAK1 by upregulating its negative regulator, IRAK3, blocking downstream inflammatory signals.
Proteostasis and the Ubiquitin-Proteasome (UP) Pathway: The UP pathway is essential for clearing damaged proteins. IBU treatment altered the expression of TLR-related ubiquitin ligases and conjugases, though these transcriptomic changes were highly sex-dependent.
cAMP Signaling: As a non-selective PDE inhibitor, IBU prevents the enzymatic breakdown of cAMP. In females specifically, IBU upregulated cAMP-specific PDE 4b and 4d, adenylate cyclase 1, and protein kinases, demonstrating a sexually dimorphic response in metabolic regulation.
Organ-Specific Aging Priorities: The dentate gyrus (DG) of the hippocampus is highly vulnerable to early aging and Alzheimer’s pathology. The study identified the DG as the primary locus of IBU’s protective effects, with significant local reductions in Aβ and tau burdens.
Novelty
Machine Learning Integration: This paper pioneers a structural systems pharmacology pipeline that integrates chemical-induced gene expression predictions with genome-wide drug-target mapping using actual human Alzheimer’s tissue data to predict repurposing efficacy.
Sex Dimorphism in Mechanism of Action: The identification of profound sex-dependent differences in how IBU alters the TLR, UP, and cAMP pathways is a novel finding not previously established in the context of Alzheimer’s pharmacology.
Critical Limitations
Translational Uncertainty: The Tg-AD rat model relies on severe, multi-fold overexpression of human genes (APPsw at 2.6-fold and PS1ΔE9 at 6.2-fold). This artificially forces rapid plaque and tangle formation, which may not accurately reflect the etiology or timeline of sporadic human Alzheimer’s disease [Confidence: High].
Incomplete Rescue (Effect-Size): While IBU mitigated cognitive deficits and reduced glial reactivity, it failed to prevent or reverse the loss of differentiated neurons within the granular cell layer of the dentate gyrus [Confidence: High].
Missing Data: The intervention was administered prophylactically (starting at 5 months of age, prior to severe pathology). The study lacks data on whether IBU can halt or reverse pathology if administered in advanced stages of the disease [Confidence: High].
External Verification: Literature confirms these exact physiological and behavioral improvements occurring in transgenic rat (Tg-AD) and mouse models following Ibudilast administration.
Translational Gap:SEVERE. This is the core translational vulnerability of the paper. Decades of Alzheimer’s research demonstrate that clearing plaques or rescuing memory in rodents rarely translates to human clinical success. There is currently no Level A or B evidence demonstrating that Ibudilast reduces amyloid burden or reverses cognitive decline in human Alzheimer’s patients.
Claim 4: Ibudilast is an approved therapeutic in Japan and other Asian countries for the treatment of asthma and stroke.
Evidence Level: Level A (Established Regulatory Fact).
External Verification: Ibudilast has been marketed in Japan (under trade names such as Ketas and Pinatos) for over two decades. It is prescribed for bronchial asthma and post-stroke dizziness, validating its long-term safety profile and blood-brain barrier permeability in humans.
Claim 5: Ibudilast treatment reduces brain atrophy in patients with progressive multiple sclerosis (MS).
Evidence Level: Level B (Human RCT).
External Verification: The Phase 2 SPRINT-MS clinical trial evaluated Ibudilast in patients with primary and secondary progressive MS. The trial successfully met its primary endpoint, demonstrating a 48% reduction in the rate of whole-brain atrophy progression compared to placebo over 96 weeks. This provides strong, human-validated evidence of the compound’s neuroprotective capabilities against chronic neuroinflammation.
Ibudilast Lowers Neuroinflammation in Alcohol Use Disorder
Alcoholism is increasingly viewed through a neuroimmune lens, where chronic alcohol consumption triggers a persistent state of neuroinflammation that drives craving and relapse. Researchers recently tested ibudilast, a neuroimmune modulator originally developed for asthma, in a two-week micro-longitudinal trial involving 52 heavy drinkers. By measuring peripheral blood markers and central neurometabolites via magnetic resonance spectroscopy (MRS), the team sought to quantify the drug’s impact on inflammation.
The data indicates that ibudilast suppresses key inflammatory signatures. Specifically, it lowered choline levels—a proxy for glial cell activation and membrane turnover—in the brain’s superior frontal white matter. Systemically, the drug nominally reduced C-reactive protein (CRP) and improved the ratio of pro-inflammatory to anti-inflammatory cytokines (TNF-a/IL-10). Most critically, subjects exhibiting the lowest choline levels post-treatment drank the least in the subsequent week, suggesting a direct link between cooling the brain’s immune response and altering addictive behavior. This provides an early, albeit incomplete, proof-of-concept that modulating the neuroimmune axis could break the cycle of addiction, offering a compelling pathway for broader anti-neuroinflammatory interventions.
Ibudilast functions as a preferential inhibitor of phosphodiesterases (PDE3A, -4, -10A, and -11A) and an allosteric inhibitor of macrophage migration inhibitory factor (MIF).
These altered nucleotide levels modulate protein kinase pathways responsible for microglial activation and neuroinflammation.
In the brain, ibudilast administration resulted in significantly lower levels of choline-containing compounds (Cho) within the superior frontal white matter (SFWM).
Elevated Cho serves as an established magnetic resonance spectroscopy (MRS) marker for accelerated cell membrane metabolism and glial cell activation.
Systemically, ibudilast induced a nominal decrease in C-reactive protein (CRP) and the TNF-a/IL-10 ratio, indicating a shift away from a pro-inflammatory state.
For the optimization of human healthspan, persistent sterile inflammation (inflammaging) is a primary driver of systemic senescence; the systemic attenuation of TNF-a and the modulation of neuroimmune pathways position PDE/MIF inhibitors as highly relevant compounds for mitigating age-related neurodegeneration. [Confidence: Medium]
Novelty
This paper provides the first in-human demonstration that ibudilast alters both central neurometabolite profiles and peripheral inflammatory markers in an AUD patient population.
The study establishes a novel biochemical-behavioral correlation: lower post-treatment Cho levels in the SFWM strictly predicted reduced alcohol consumption within the ibudilast cohort.
Critical Limitations
The two-week trial duration is fundamentally inadequate to establish long-term neuroprotective efficacy or sustained anti-inflammatory action.
The sample size for the MRS analysis was statistically modest (n=43), increasing the risk of Type II errors.
Neurometabolite data were acquired cross-sectionally at the midpoint (Study Day 2), lacking a pre-randomization baseline scan; this precludes definitive causal claims regarding the drug’s ability to actively reduce pre-existing neurometabolite levels.
Peripheral cytokine results were confounded by unexpected, spontaneous drops in IL-8 within the placebo group, obscuring the true magnitude of the treatment effect.
The trial failed to include a healthy control cohort, preventing a comparative baseline analysis of standard inflammatory markers against non-AUD physiology.
Looks like an interesting drug. We would need to look at the literature to see if it might be useful in preventative capacity, as that’s not the same thing as clinical use for indicated conditions as outlined above.