FHL-201 & 301
FHL-201 is an organic compound found in many plants and is shown in both Parkinson’s disease (PD) and Alzheimer’s disease (AD) animal models to exert therapeutic effects through the activation of peroxisome proliferator-activated receptor alpha (PPARα) agonist, similar to the mechanism of action demonstrated by FHL-301.
FHL-201 has clearly demonstrated to restore striatal neurotransmitters and improve locomotive behaviors in PD animal model. Furthermore, FHL-201 has shown therapeutic effects to stimulate lysosomal biogenesis to treat AD progression.
FHL-301 is a repurposed drug acting as a PPARα agonist which activates PPARα that binds to specific DNA sequences called peroxisome proliferator response elements (PPREs) located in the promoter region of the target gene, thereby upregulating Transcription Factor EB (TFEB) expression.
Deposition of extracellular senile plaques containing amyloid is one of the major neuropathological characteristics of AD. Therefore, targeting amyloid-dyshomeostasis is an important therapeutic strategy for treatment of AD. FHL-301, a repurposed, FDA approved drug works to lower the amyloid plaque burden in the hippocampus and cortex of the 5XFAD murine model of AD.
Additionally, FHL-301 is shown to reduce microgliosis and astrogliosis associated with plaque in these mice. Administration of the drug also improves spatial learning and memory of the 5XFAD mice.
In addition, it is understood that hexadecanamide (Hex) is present in vivo in hippocampal nuclei of normal mice as an endogenous ligand of PPARα. FHL-301, through PPARα activation, induces Hex which upregulates brain-drived neurotrophic factors (BDNF), protecting hippocampal neurons, resulting in therapeutic effects for AD.