Dihexa was built by university researchers as a stand-in for a natural brain chemical called HGF (hepatocyte growth factor), which helps brain cells grow and connect to each other. Unlike the natural version, dihexa can be taken by mouth and can get into the brain, which made it exciting to scientists studying Alzheimer's and other memory problems. Its whole track record comes from mice, rats, zebrafish, and lab dishes - there is no published human trial. Some people buy it online as an unregulated "research chemical" nootropic, but that use is not backed by any human evidence at all.
How strong is the evidence?
Every study on dihexa is an animal experiment, a lab-dish experiment, or a review summarizing that animal work - there is not one published human trial. The animal results for memory and brain-cell growth are fairly consistent across several independent labs, but dihexa also flatly failed in one disease model (Huntington's disease in rats), which is an important reality check. Because there is zero human testing, anything said about dihexa's effects, dose, or safety in people is a guess, not a finding.
Uses
What people use it for
Alzheimer's-type memory loss (mouse studies)
Animal / labIn mice bred to develop Alzheimer's-like brain plaques, dihexa restored the ability to learn a water maze, grew more brain cells, and calmed down brain inflammation.
General memory and learning problems (rat studies)
Animal / labThe original dihexa studies gave it by mouth to rats with drug-induced memory loss and to naturally aged rats, and it reversed their memory problems while growing new connections between brain cells.
Nerve injury recovery (rat studies)
Animal / labWhen rats had a leg nerve cut and surgically repaired, dihexa combined with stem cells helped their leg muscles work better during recovery. The improvement showed up for the stem-cell-plus-dihexa combination, not for dihexa on its own.
Protecting hearing cells from toxic drugs (fish/lab studies)
Animal / labIn zebrafish, a common stand-in for testing inner-ear hair cells, dihexa protected sound-sensing cells from damage caused by certain antibiotics and chemotherapy drugs.
Sold online as a human cognitive-enhancement 'research chemical'
AnecdotalBecause of its dramatic animal results, dihexa is marketed by some online sellers as a memory or focus booster for people. This use has never been studied in a human trial and is not something researchers have vetted.
Potential benefits
What it may help with
Memory and learning improvements in animals
Animal / labAcross several independent rat and mouse studies, dihexa reversed drug-induced memory loss, restored learning in aged and Alzheimer's-model animals, and did this consistently enough that multiple labs reproduced it.
Grows new connections between brain cells
Animal / labDihexa increases the number and branching of the tiny connection points (synapses) between brain cells, which is the biological basis researchers think explains its memory effects.
Calms brain inflammation in an Alzheimer's mouse model
Animal / labIn Alzheimer's-model mice, dihexa lowered inflammatory signals in the brain and increased a calming, anti-inflammatory one, alongside its memory benefits.
Studies:34827486May help nerves and hearing cells recover from damage
Animal / labBeyond memory, dihexa helped rats regain leg function after nerve surgery and protected fish hearing cells from toxic drug exposure - suggesting a broader cell-protecting and cell-repairing effect tied to the same growth-factor pathway.
What to watch for
Side effects & risks
- Moderate
Human safety is completely unknown
No human trial has ever given dihexa to a person, so there is no real-world data on side effects, safe dose ranges, or long-term risks in people.
- Moderate
Theoretical cell-growth concern from its growth-factor pathway
Dihexa works by switching on a growth-factor pathway (HGF/c-Met) that also drives cell growth and division throughout the body - the studies cited here document that growth-promoting mechanism. In the wider medical literature, an overactive c-Met pathway is a known feature of some cancers, so deliberately turning this signal up with an unregulated compound is a theoretical safety concern. Importantly, no study has actually tested whether dihexa raises cancer risk, and none of the cited papers report a cancer link - this is caution based on how the pathway behaves, not a measured effect of dihexa.
- Mild
Did not work in a Huntington's disease animal model
In rats with Huntington's disease-like damage, dihexa did not protect against weight loss, movement problems, or memory deficits - a reminder that its benefits don't automatically carry over to every brain condition.
Dosing
Dosing — what studies used
There is no established human dose for dihexa - it has never been given to a person in a published study, so any amount sold online is not based on real dosing research. The doses below are strictly what researchers used in animals and lab dishes; they are not a recommendation and cannot be safely scaled to a person.
Nerve injury recovery after sciatic nerve repair (rat model)
Animal study2-4 mg per kg of body weight
Given locally via hydrogel at the repair site, systemically (IV/IP), and into the calf muscle, in different treatment groups · Followed for up to 16 weeks after nerve repair surgery · Injection (IV/IP), local hydrogel, intramuscular
Often combined with stem cells and/or a growth-factor drug (G-CSF) rather than used alone. This is a rat dose, not a human one.
Protecting hair (ear sensory) cells from ototoxic antibiotics (zebrafish lab model)
Animal study1 micromolar concentration in the surrounding water
Single acute exposure · Short-term, acute exposure test · Bath/immersion (lab dish exposure, not a body dose)
This is a lab concentration used to bathe fish larvae, not a dose a person could replicate or take.
The foundational rat memory studies describe oral dosing in scopolamine-treated and aged rats but the published abstracts don't spell out an exact milligram amount, so no number is given here rather than guessing. Dihexa is not an approved medicine anywhere, so there is no official drug label to fall back on.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
Your body makes a natural signal called HGF that tells cells to grow, connect, and repair - but HGF is a large molecule that can't cross into the brain and breaks down fast if swallowed. Dihexa is a small, stable, mouth-active copy that plugs into the same docking station on cells, called the c-Met receptor, and switches on the same growth signal. In the brain, turning on this signal seems to help neurons sprout new connections to each other (the physical basis of learning and memory). Because dihexa can be swallowed and still get into the brain - something the natural HGF signal can't do - it became a research tool for testing whether boosting this pathway could treat memory disorders.
Who should avoid it
- Anyone with cancer or a history of cancer should avoid it - the growth-factor pathway it activates is also studied as a driver of some cancers, and this has never been ruled out for dihexa.
- Pregnant or breastfeeding people should avoid it, since there is no safety data of any kind.
- Children should not use it - there is no pediatric data whatsoever.
- Anyone already on an experimental growth-factor or HGF/c-Met-pathway treatment should avoid combining it without medical guidance.
- Anyone expecting a specific human effect or dose should treat it as unproven, since it has never been tested in people.
Interactions to know
- No human drug-interaction studies exist for dihexa at all.
- Theoretical concern with other drugs that act on the same HGF/c-Met growth-factor pathway, including some experimental cancer therapies, since dihexa works through that same signal.
The papers that matter most
Key studies
The paper that created dihexa. Oral dosing reversed drug-induced and age-related memory loss in rats and grew new brain-cell connections.
Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents.
Pinpointed how dihexa works: it activates the brain's HGF/c-Met growth-factor system, and blocking that system erased dihexa's memory benefits.
The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system.
In mice engineered to develop Alzheimer's-like disease, dihexa restored memory, grew more neurons, and reduced brain inflammation.
AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway.
In a Huntington's disease rat model, dihexa did not help at all - an honest counterweight to the positive Alzheimer's-model results.
Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.
Showed a different potential use: protecting sound-sensing hair cells from damage caused by certain antibiotics and chemotherapy drugs.
Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure.
After nerve injury and surgical repair, rats given dihexa (often paired with stem cells) recovered leg function better than untreated controls.
Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies.
Bottom line
Dihexa has a genuinely interesting backstory in brain-growth-factor science and consistent memory benefits in mice and rats, but it has never been given to a person in a real study, so nobody knows the right human dose, whether it's safe, or whether it even works in people. Treat it as an experimental research compound to watch, not something to take.
Research papers
Studies we have on file for Dihexa. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
17 papers
Therapeutic Peptides in Orthopaedics: Applications, Challenges, and Future Directions.
Therapeutic peptides are emerging as promising adjuncts in the management of orthopaedic injuries, grounded in their ability to modulate molecular signaling networks central to cellular medicine. By acting on key pathways such as PI3K/Akt, mTOR, MAPK, TGF-β, and AMPK, peptides exert influence over tissue regeneration, inflammation resolution, and neuromuscular recovery. Wound-healing peptides such as BPC-157, TB-500, and GHK-Cu promote angiogenesis, integrin-mediated extracellular matrix remodeling, and fibroblast activation, whereas growth hormone secretagogues like ipamorelin, CJC-1295, tesamorelin, sermorelin, and AOD-9604 activate IGF-1 signaling and satellite cell repair. Recovery-enhancing agents such as epithalon, delta sleep-inducing peptide, and pinealon target circadian and mitochondrial regulators, and neuroactive peptides like selank, semax, and dihexa enhance brain-derived neurotrophic factor and HGF/c-Met pathways critical to neuroplasticity. Although preclinical studies are promising, there is a current lack of clinical trials. This review integrates current mechanistic insights with orthopaedic relevance, emphasizing safety, efficacy, and future directions for responsible integration into musculoskeletal care.
Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.
Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD. The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent. Forty male Wistar rats were randomized into three groups consisting of a "vehicle" group, a "3-NP" group, and a "3-NP + PNB-0408" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis. Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity. Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.
Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure.
Loss of sensory hair cells from exposure to certain licit drugs (e.g., aminoglycoside antibiotics, platinum-based chemotherapy agents) can result in permanent hearing loss. Here we ask if allosteric activation of the hepatocyte growth factor (HGF) cascade via Dihexa, a small molecule drug candidate, can protect hair cells from aminoglycoside toxicity. Unlike native HGF, Dihexa is chemically stable and blood-brain barrier permeable. As a synthetic HGF mimetic, it forms a functional ligand by dimerizing with endogenous HGF to activate the HGF receptor and downstream signaling cascades. To evaluate Dihexa as a potential hair cell protectant, we used the larval zebrafish lateral line, which possesses hair cells that are homologous to mammalian inner ear hair cells and show similar responses to toxins. A dose-response relationship for Dihexa protection was established using two ototoxins, neomycin and gentamicin. We found that a Dihexa concentration of 1 μM confers optimal protection from acute treatment with either ototoxin. Pretreatment with Dihexa does not affect the amount of fluorescently tagged gentamicin that enters hair cells, indicating that Dihexa's protection is likely mediated by intracellular events and not by inhibiting aminoglycoside entry. Dihexa-mediated protection is attenuated by co-treatment with the HGF antagonist 6-AH, further evidence that HGF activation is a component of the observed protection. Additionally, Dihexa's robust protection is partially attenuated by co-treatment with inhibitors of the downstream HGF targets Akt, TOR and MEK. Addition of an amino group to the N-terminal of Dihexa also attenuates the protective response, suggesting that even small substitutions greatly alter the specificity of Dihexa for its target. Our data suggest that Dihexa confers protection of hair cells through an HGF-mediated mechanism and that Dihexa holds clinical potential for mitigating chemical ototoxicity.
The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disease increasing in frequency as life expectancy of the world's population increases. There are an estimated 5 million diagnosed AD patients in the U.S. and 16 million worldwide with no adequate treatment presently available. New therapeutic approaches are needed to slow, and hopefully reverse, disease progression. This review summarizes available information regarding an overlooked therapeutic target that may offer a treatment to slow and hopefully halt AD, namely the hepatocyte growth factor (HGF)/c-Met receptor system. Activation of the c-Met receptor stimulates mitogenesis, motogenesis, morphogenesis, the ability to mediate stem cell differentiation and neurogenesis, and protects against tissue insults in a wide range of cells including neurons. This growth factor system has recently been shown to induce dendritic arborization and synaptogenesis when stimulated by a newly developed angiotensin-based analogue, N-hexanoic-Tyr-Ile-(6) amino hexanoic amide (Dihexa). This small molecule was derived from the pre-prototype molecule Nle1-angiotensin IV and has shown promise in facilitating the formation of new functional synaptic connections and augmenting memory consolidation in animal models of AD. Dihexa is a first-in-class compound that is orally active, penetrates the blood-brain barrier, and facilitates memory consolidation and retrieval. This angiotensin-based small molecule may be efficacious as a treatment for AD.
The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system.
A subset of angiotensin IV (AngIV)-related molecules are known to possess procognitive/antidementia properties and have been considered as templates for potential therapeutics. However, this potential has not been realized because of two factors: 1) a lack of blood-brain barrier-penetrant analogs, and 2) the absence of a validated mechanism of action. The pharmacokinetic barrier has recently been overcome with the synthesis of the orally active, blood-brain barrier-permeable analog N-hexanoic-tyrosine-isoleucine-(6) aminohexanoic amide (dihexa). Therefore, the goal of this study was to elucidate the mechanism that underlies dihexa's procognitive activity. Here, we demonstrate that dihexa binds with high affinity to hepatocyte growth factor (HGF) and both dihexa and its parent compound Norleucine 1-AngIV (Nle(1)-AngIV) induce c-Met phosphorylation in the presence of subthreshold concentrations of HGF and augment HGF-dependent cell scattering. Further, dihexa and Nle(1)-AngIV induce hippocampal spinogenesis and synaptogenesis similar to HGF itself. These actions were inhibited by an HGF antagonist and a short hairpin RNA directed at c-Met. Most importantly, the procognitive/antidementia capacity of orally delivered dihexa was blocked by an HGF antagonist delivered intracerebroventricularly as measured using the Morris water maze task of spatial learning.
Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies.
Optimizing nerve regeneration and re-innervation of target muscle/s is the key for improved functional recovery following peripheral nerve damage. We investigated whether administration of mesenchymal stem cell (MSC), Granulocyte-Colony Stimulating Factor (G-CSF) and/or Dihexa can improve recovery of limb function following peripheral nerve damage in rat sciatic nerve transection-repair model. There were 10 experimental groups (n = 6-8 rats/group). Bone marrow derived syngeneic MSCs (2 × 106; passage≤6), G-CSF (200-400 μg/kg b.wt.), Dihexa (2-4 mg/kg b.wt.) and/or Vehicle were administered to male Lewis rats locally via hydrogel at the site of nerve repair, systemically (i.v./i.p), and/or to gastrocnemius muscle. The limb sensory and motor functions were assessed at 1-2 week intervals post nerve repair until the study endpoint (16 weeks). The sensory function in all nerve boundaries (peroneal, tibial, sural) returned to nearly normal by 8 weeks (Grade 2.7 on a scale of Grade 0-3 [0 = No function; 3 = Normal function]) in all groups combined. The peroneal nerve function recovered quickly with return of function at one week (∼2.0) while sural nerve function recovered rather slowly at four weeks (∼1.0). Motor function at 8-16 weeks post-nerve repair as determined by walking foot print grades significantly (P < 0.05) improved with MSC + G-CSF or MSC + Dihexa administrations into gastrocnemius muscle and mitigated foot flexion contractures. These findings demonstrate MSC, G-CSF and Dihexa are promising candidates for adjunct therapies to promote limb functional recovery after surgical nerve repair, and have implications in peripheral nerve injury and limb transplantation. IACUC No.215064.
Dimeric DOTA-alpha-melanocyte-stimulating hormone analogs: synthesis and in vivo characteristics of radiopeptides with high in vitro activity.
Dimeric analogs of alpha-melanocyte-stimulating hormone (alpha-MSH) labeled with radiometals are potential candidates for diagnosis and therapy of melanoma by receptor-mediated tumor targeting. Both melanotic and amelanotic melanomas (over-)express the melanocortin-1 receptor (MC1-R), the target for alpha-MSH. In the past, dimerized MSH analogs have been shown to display increased receptor affinity compared to monomeric MSH, offering the possibility of improving the ratio between specific uptake of radiolabeled alpha-MSH by melanoma and nonspecific uptake by the kidneys. We have designed three linear dimeric analogs containing a slightly modified MSH hexapeptide core sequence (Nle-Asp-His-d-Phe-Arg-Trp) in parallel or antiparallel orientation, a short spacer, and the DOTA chelator for incorporation of the radiometal. In vitro, all three peptides were more potent ligands of the mouse B16-F1 melanoma cell melanocortin-1 receptor (MC1-R) than DOTA-NAPamide, which served as standard. The binding activity of DOTA-diHexa(NC-NC)-amide was 1.75-fold higher, that of diHexa(NC-NC)-Gly-Lys(DOTA)-amide was 3.37-fold higher, and that of DOTA-diHexa(CN-NC)-amide was 2.34-fold higher. Using human HBL melanoma cells, the binding activity of diHexa(NC-NC)-Gly-Lys(DOTA)-amide was sixfold higher than that of DOTA-NAPamide. Uptake by cultured B16-F1 cells was rapid and almost quantitative. In vivo, however, the data were less promising: tumor-to-kidney ratios 4 hr postinjection were 0.11 for [(111)In]DOTA-diHexa(NC-NC)-amide, 0.26 for diHexa(NC-NC)-Gly-Lys([(111)In]DOTA)-amide, and 0.36 for [(111)In]DOTA-diHexa(CN-NC)-amide, compared to 1.67 for [(111)In]DOTA-NAPamide. It appears that despite the higher affinity to the MC1-R of the peptide dimers and their excellent internalization in vitro, the uptake by melanoma tumors in vivo was lower, possibly because of reduced tissue penetration. More striking, however, was the marked increase of kidney uptake of the dimers, explaining the unfavorable ratios. In conclusion, although radiolabeled alpha-MSH dimer peptides display excellent receptor affinity and internalization, they are no alternative to the monomeric DOTA-NAPamide for in vivo application.
Efficiently generate functional hepatic cells from human pluripotent stem cells by complete small-molecule strategy.
Various methods have been developed to generate hepatic cells from human pluripotent stem cells (hPSCs) that rely on the combined use of multiple expensive growth factors, limiting industrial-scale production and widespread applications. Small molecules offer an attractive alternative to growth factors for producing hepatic cells since they are more economical and relatively stable. We dissect small-molecule combinations and identify the ideal cocktails to achieve an optimally efficient and cost-effective strategy for hepatic cells differentiation, expansion, and maturation. We demonstrated that small-molecule cocktail CIP (including CHIR99021, IDE1, and PD0332991) efficiently induced definitive endoderm (DE) formation via increased endogenous TGF-β/Nodal signaling. Furthermore, we identified that combining Vitamin C, Dihexa, and Forskolin (VDF) could substitute growth factors to induce hepatic specification. The obtained hepatoblasts (HBs) could subsequently expand and mature into functional hepatocyte-like cells (HLCs) by the established chemical formulas. Thus, we established a stepwise strategy with complete small molecules for efficiently producing scalable HBs and functionally matured HLCs. The small-molecule-derived HLCs displayed typical functional characteristics as mature hepatocytes in vitro and repopulating injured liver in vivo. Our current small-molecule-based hepatic generation protocol presents an efficient and cost-effective platform for the large-scale production of functional human hepatic cells for cell-based therapy and drug discovery using.
Small-Molecule-Directed Hepatocyte-Like Cell Differentiation of Human Pluripotent Stem Cells.
Hepatocyte-like cells (HLCs) generated in vitro from human pluripotent stem cells (hPSCs) provide an invaluable resource for basic research, regenerative medicine, drug screening, toxicology, and modeling of liver disease and development. This unit describes a small-molecule-driven protocol for in vitro differentiation of hPSCs into HLCs without the use of growth factors. hPSCs are coaxed through a developmentally relevant route via the primitive streak to definitive endoderm (DE) using the small molecule CHIR99021 (a Wnt agonist), replacing the conventional growth factors Wnt3A and activin A. The small-molecule-derived DE is then differentiated to hepatoblast-like cells in the presence of dimethyl sulfoxide. The resulting hepatoblasts are then differentiated to HLCs with N-hexanoic-Tyr, Ile-6 aminohexanoic amide (Dihexa, a hepatocyte growth factor agonist) and dexamethasone. The protocol provides an efficient and reproducible procedure for differentiation of hPSCs into HLCs utilizing small molecules. © 2016 by John Wiley & Sons, Inc.
AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway.
The renin-angiotensin system (RAS) is a paracrine RAS within the central nervous system (CNS) and is closely related to Alzheimer's disease (AD). The endogenous hexapeptide angiotensin IV (Ang IV), an important component of the brain RAS, was found to rescue cognitive impairment and recover memory in previous studies. In our study, we used different doses of Dihexa, which can be orally administered and cross the BBB in APP/PS1 mice. We found that the amount of AngIV in mouse tissue increased after the administration of Dihexa compared to that in the WT group. Meanwhile, Dihexa restored spatial learning and cognitive functions in the Morris water maze test. Dihexa increased the neuronal cells and the expression of SYP protein in APP/PS1 mice in Nissl staining. Furthermore, Dihexa decreased the activation of astrocytes and microglia, markedly reduced levels of the pro-inflammatory cytokines IL-1β and TNF-α and increased the levels of the anti-inflammatory cytokine IL-10. Dihexa activated the PI3K/AKT signaling pathway, while PI3K inhibitor wortmannin significantly reversed the anti-inflammatory and anti-apoptotic effects of APP/PS1 mice. These findings highlight the brain AngIV/PI3K/AKT axis as a potential target for the treatment of AD.
Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies.
To explore effects of the brain renin-angiotensin system (RAS) on cognition. Systematic review of experimental (non-human) studies assessing cognitive effects of RAS peptides angiotensin-(3-8) [Ang IV] and angiotensin-(1-7) [Ang-(1-7)] and their receptors, the Ang IV receptor (AT4R) and the Mas receptor. Of 450 articles identified, 32 met inclusion criteria. Seven of 11 studies of normal animals found Ang IV had beneficial effects on tests of passive or conditioned avoidance and object recognition. In models of cognitive deficit, eight of nine studies found Ang IV and its analogs (Nle1-Ang IV, dihexa, LVV-hemorphin-7) improved performance on spatial working memory and passive avoidance tasks. Two of three studies examining Ang-(1-7) found it benefited memory. Mas receptor removal was associated with reduced fear memory in one study. Studies of cognitive impairment show salutary effects of acute administration of Ang IV and its analogs, as well as AT4R activation. Brain RAS peptides appear most effective administered intracerebroventricularly, close to the time of learning acquisition or retention testing. Ang-(1-7) shows anti-dementia qualities.
The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases.
Alzheimer's (AD) and Parkinson's (PD) diseases are neurodegenerative diseases presently without effective drug treatments. AD is characterized by general cognitive impairment, difficulties with memory consolidation and retrieval, and with advanced stages episodes of agitation and anger. AD is increasing in frequency as life expectancy increases. Present FDA approved medications do little to slow disease progression and none address the underlying progressive loss of synaptic connections and neurons. New drug design approaches are needed beyond cholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists. Patients with PD experience the symptomatic triad of bradykinesis, tremor-at-rest, and rigidity with the possibility of additional non-motor symptoms including sleep disturbances, depression, dementia, and autonomic nervous system failure. This review summarizes available information regarding the role of the brain renin-angiotensin system (RAS) in learning and memory and motor functions, with particular emphasis on research results suggesting a link between angiotensin IV (AngIV) interacting with the AT4 receptor subtype. Currently there is controversy over the identity of this AT4 receptor protein. Albiston and colleagues have offered convincing evidence that it is the insulin-regulated aminopeptidase (IRAP). Recently members of our laboratory have presented evidence that the brain AngIV/AT4 receptor system coincides with the brain hepatocyte growth factor/c-Met receptor system. In an effort to resolve this issue we have synthesized a number of small molecule AngIV-based compounds that are metabolically stable, penetrate the blood-brain barrier, and facilitate compromised memory and motor systems. These research efforts are described along with details concerning a recently synthesized molecule, Dihexa that shows promise in overcoming memory and motor dysfunctions by augmenting synaptic connectivity via the formation of new functional synapses.
Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents.
Angiotensin IV (AngIV: VYIHPF)-related peptides have long been recognized as procognitive agents with potential as antidementia therapeutics. Their development as useful therapeutics, however, has been limited by physiochemical properties that make them susceptible to metabolic degradation and impermeable to gut and blood-brain barriers. A previous study demonstrated that the core structural information required to impart the procognitive activity of the AngIV analog, norleucine(1)-angiotensin IV, resides in its three N-terminal amino acids, Nle-Tyr-Ile. The goal of this project was to chemically modify this tripeptide in such a way to enhance its metabolic stability and barrier permeability to produce a drug candidate with potential clinical utility. Initial results demonstrated that several N- and C-terminal modifications lead to dramatically improved stability while maintaining the capability to reverse scopolamine-induced deficits in Morris water maze performance and augment hippocampal synaptogenesis. Subsequent chemical modifications, which were designed to increase hydrophobicity and decrease hydrogen bonding, yielded an orally active, blood-barrier permeant, metabolically stabilized analog, N-hexanoic-Tyr-Ile-(6) aminohexanoic amide (dihexa), that exhibits excellent antidementia activity in the scopolamine and aged rat models and marked synaptogenic activity. These data suggest that dihexa may have therapeutic potential as a treatment of disorders, such as Alzheimer's disease, where augmented synaptic connectivity may be beneficial.
Studies on the subcellular localization of the porphycene CPO.
This study was designed to provide more detailed information on the subcellular sites of binding of the porphycene, termed 9-capronyloxytetrakis (methoxyethyl) porphycene (CPO), with a fluorescence resonance energy transfer (FRET) technique. The proximity of CPO to two fluorescent probes was determined: nonyl acridine orange (NAO), a dye with specific affinity for the mitochondrial lipid cardiolipin, and dihexa-oxacarbocyanine iodide (DiOC6), an agent that labels the endoplasmic reticulum (ER). FRET spectra indicated energy transfer between DiOC6 and CPO but no significant transfer between NAO and CPO. These results confirm data obtained by fluorescence microscopy, suggesting a similar pattern of subcellular localization by CPO and DiOC6 but not by CPO and NAO. However, when cells containing CPO were irradiated and then loaded with NAO, FRET between the two fluorophores was observed. Hence, a relocalization of CPO can occur during irradiation. These data provide an explanation for recent studies on CPO-catalyzed photodamage to both ER and mitochondrial Bcl-2.
Effect of structure on the interactions between five natural antimicrobial compounds and phospholipids of bacterial cell membrane on model monolayers.
Monolayers composed of bacterial phospholipids were used as model membranes to study interactions of the naturally occurring phenolic compounds 2,5-dihydroxybenzaldehyde and 2-hydroxy-5-methoxybenzaldehyde, and the plant essential oil compounds carvacrol, cinnamaldehyde, and geraniol, previously found to be active against both Gram-positive and Gram-negative pathogenic microorganisms. The lipid monolayers consist of 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1,2-dihexa- decanoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG), and 1,1',2,2'-tetratetradecanoyl cardiolipin (cardiolipin). Surface pressure-area (π-A) and surface potential-area (Δψ-A) isotherms were measured to monitor changes in the thermodynamic and physical properties of the lipid monolayers. Results of the study indicated that the five compounds modified the three lipid monolayer structures by integrating into the monolayer, forming aggregates of antimicrobial -lipid complexes, reducing the packing effectiveness of the lipids, increasing the membrane fluidity, and altering the total dipole moment in the monolayer membrane model. The interactions of the five antimicrobial compounds with bacterial phospholipids depended on both the structure of the antimicrobials and the composition of the monolayers. The observed experimental results provide insight into the mechanism of the molecular interactions between naturally-occurring antimicrobial compounds and phospholipids of the bacterial cell membrane that govern activities.
Localization of alveolar surfactant clearance in rabbit lung cells.
Localization of surfactant phospholipid clearance in lung cells was investigated in vivo in rabbits using radiolabeled dipalmitoylphosphatidylcholine (DPPC) and 1,2-dihexa-decyl-sn-glycero-3-phosphocholine (DPPC-ether), a phospholipase A1- and A2-resistant analogue of DPPC. After intratracheal injection of liposomes of the labeled lipids associated with unlabeled surfactant, adult rabbits were killed in groups of three to five at 0, 4, 12, and 24 h with recovery of bronchoalveolar lavages for alveolar macrophages and surfactant. Type II cells and tissue-associated macrophages were isolated on Percoll gradients following elastase and trypsin digestion of the lungs. Radiolabel recoveries as saturated phosphatidylcholine were measured in alveolar wash, alveolar macrophages, lung tissue, and the type II cell and mixed cell bands from the Percoll gradients. Cost accounting of label demonstrated similar recoveries at 0 h, but significantly more DPPC-ether compared with DPPC in cells at later times, indicating ineffective degradation of the DPPC-ether. Internalization of the lung tissue-associated labels into cells was time dependent. At all times, greater than 65% of the cell-associated labels were recovered in type II cells, indicating the primary role for these cells in clearing alveolar surfactant phospholipid in vivo. The total contribution of alveolar macrophages to the overall clearance was approximately 20%.
Phase segregation of polymerizable lipids to construct filters for separating lipid-membrane-embedded species.
Supported lipid bilayer (SLB) platforms have been developed to transport and separate membrane-embedded species in the species' native bilayer environment. In this study, we used the phase segregation phenomenon of lipid mixtures containing a polymerizable diacetylene phospholipid, 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DiynePC), and a nonpolymerizable phospholipid, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), to create filter barrier structures in SLBs. Upon exposing the phase segregated samples to UV light, the DiynePC-rich domains could become crosslinked and remain fixed on the surface of the support, while the DOPC-rich regions, where no crosslinking could happen, could be removed later by detergent washing, and thus became the void regions in the filter. During the filter fabrication process, we used the laminar flow configuration in a microfluidic channel to control the spatial locations of the feed region and filter region in the SLB. The flow in a microfluidic channel was also used to apply a strong hydrodynamic shear stress to the SLB to transport the membrane-embedded species from the feed region to the filter region. We varied the DiynePC/DOPC molar ratio from 60/40 to 80/20 to adjust the cutoff size of the filter barriers and used two model membrane-embedded species of different sizes to examine the filtering capability. One of the model species, Texas Red 1,2-dihexa-decanoyl-sn-glycero-3-phosphoethanolamine triethylammonium salt (Texas Red DHPE), had a single-lipid size, and the other species, cholera toxin subunit B-GM1 complex, had a multilipid size. When the DiynePC/DOPC molar ratio was 60/40, both species had high penetration ratios in the filter region. However, when the ratio was increased to 70/30, only the Texas Red DHPE, which was the smaller of the two model species, could penetrate the filter to a considerable extent. When the ratio was increased to 80/20, neither of the model species could penetrate the filter region. The results showed the possibility of using phase segregation of a mixture containing a polymerizable lipid and a nonpolymerizable lipid to fabricate filter barrier structures with tunable cutoff sizes in SLBs.
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