Purmorphamine mitigates 3-nitropropionic acid-induced neurodegeneration via enhancing the brain-derived neurotrophic factor/protein kinase B/glycogen synthase kinase-3β signaling and attenuation of oxidative/nitrosative stress, neuroinflammation, and apoptosis.

Huntington disease (HD) is a progressive neurodegenerative condition marked by characteristic motor deficits, cognitive decline, and psychiatric disturbances. The mitochondrial toxin 3-nitropropionic acid (3-NP) reliably replicates the HD pathological features by inducing selective striatal and cortical neurodegeneration. Increasing evidence indicates that activation of the Sonic Hedgehog (Shh) signaling could enhance neurotrophic and prosurvival signaling, particularly through modulation of the brain-derived neurotrophic factor (BDNF)/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) cascade. Via activation of the Shh pathway, purmorphamine (PUR)-the smoothened agonist-may offer a therapeutic benefit against HD-like pathology. However, its in vivo efficacy in 3-NP neurotoxicity remains unexplored. To examine this possibility, 48 male Wistar rats were assigned to control, PUR, 3-NP, and 3-NP/PUR groups and treated daily for 21 days. Behavioral performance was assessed using the open field, rotarod, novel object recognition, and Morris water maze (MWM) tests, whereas hippocampal, prefrontal, and striatal tissues were evaluated for Shh pathway gene expression, BDNF/Akt/GSK-3β signaling, oxidative/nitrosative stress markers, and histopathological alterations. PUR markedly improved 3-NP induced motor and cognitive deficits, alleviated the BDNF/Akt/GSK-3β signaling, and attenuated oxidative/nitrosative stress, neuroinflammation, and apoptosis. In conclusion, to the best of our knowledge, these findings provide the first evidence that purmorphamine affords significant neuroprotection against 3-NP induced neurodegeneration by activating Shh-dependent BDNF/Akt/GSK-3β signaling and mitigating the key pathological processes, highlighting its promise as a potential therapeutic agent for HD-related neuropathology. SIGNIFICANCE STATEMENT: This study provides the first in vivo evidence that purmorphamine, a Sonic Hedgehog pathway agonist, effectively mitigates 3-nitropropionic acid-induced neurodegeneration by restoring the brain-derived neurotrophic factor/protein kinase B/glycogen synthase kinase-3β signaling cascade. By addressing core pathological features such as motor deficits, cognitive decline, and neuroinflammation, these findings highlight the therapeutic potential of targeting the Sonic Hedgehog pathway as a multitarget strategy for managing Huntington disease-like neurodegenerative conditions.