Dihexa: A Novel Therapeutic Agent for Neurodegenerative Diseases
Dihexa is a small molecule angiotensin IV analog that shows promise as a potential treatment for Alzheimer's disease and other neurodegenerative conditions through its ability to enhance synaptic connectivity and improve cognitive function. 1, 2
Mechanism of Action
- Dihexa functions as a hepatocyte growth factor (HGF) mimetic, forming a functional ligand by dimerizing with endogenous HGF to activate the HGF receptor (c-Met) and downstream signaling cascades 1, 3
- It activates the PI3K/AKT signaling pathway, which mediates its neuroprotective and anti-inflammatory effects 4
- Unlike native HGF, Dihexa is chemically stable and blood-brain barrier permeable, making it suitable for oral administration 3, 2
Therapeutic Potential
- Dihexa facilitates the formation of new functional synaptic connections (synaptogenesis) and dendritic arborization in animal models of Alzheimer's disease 1, 3
- It has demonstrated ability to augment memory consolidation and retrieval in animal models of cognitive impairment 1, 2
- Research shows Dihexa can restore spatial learning and cognitive functions in APP/PS1 mice (an Alzheimer's disease model) 4
- It provides protection against aminoglycoside-induced hair cell damage, suggesting potential applications in preventing hearing loss 5
Neuroprotective Effects
- Dihexa decreases activation of astrocytes and microglia in animal models, reducing neuroinflammation 4
- It reduces levels of pro-inflammatory cytokines (IL-1β and TNF-α) while increasing anti-inflammatory cytokine (IL-10) levels 4
- The compound induces hippocampal spinogenesis and synaptogenesis similar to HGF itself 3
- Dihexa increases neuronal cells and the expression of synaptophysin (SYP) protein, a marker of synaptic density 4
Pharmacological Properties
- Dihexa is orally active and penetrates the blood-brain barrier effectively 1, 3
- Its chemical structure is N-hexanoic-Tyr-Ile-(6) amino hexanoic amide, derived from the pre-prototype molecule Nle1-angiotensin IV 1
- Even small substitutions to its structure (such as adding an amino group to the N-terminal) can significantly alter its protective properties 5
- Optimal dosing appears to be concentration-dependent, with studies showing 1 μM providing optimal protection in certain experimental models 5
Current Research Status
- Dihexa is considered a first-in-class compound that shows promise for treating neurodegenerative conditions 1, 2
- It has shown efficacy in multiple animal models of Alzheimer's disease and other neurological conditions 4, 3, 2
- The compound's effects can be attenuated by HGF antagonists and inhibitors of downstream targets including Akt, TOR, and MEK, confirming its mechanism of action 5, 3
Clinical Implications
- Dihexa represents a novel approach to treating neurodegenerative diseases beyond traditional approaches like cholinesterase inhibitors and NMDA receptor antagonists 2
- Its ability to enhance synaptic connectivity addresses the underlying progressive loss of synaptic connections and neurons in Alzheimer's disease 1, 2
- The compound's oral bioavailability and blood-brain barrier penetration make it potentially suitable for clinical applications 3, 2
While Dihexa shows significant promise in preclinical studies, it is important to note that the evidence presented is primarily from animal models, and human clinical trials would be necessary to establish its safety and efficacy in treating neurodegenerative diseases in humans.