CHF6467 Exerts Neuroprotective Effects in the Rat Model of Acute Ischemic Stroke

Objectives: The critical role of nerve growth factor (NGF) in neuroprotection has been demonstrated in preclinical models of neuronal injury. Here, we investigated the neuroprotective effects of intranasal CHF6467, a recombinant mutant form of human NGF lacking algogenic activity, in transient (45 min) middle cerebral artery occlusion (tMCAo). Methods: Male Wistar rats (n = 20 per group) were treated intranasally with CHF6467 (20 µg/kg, 40 µL) or vehicle (0.9% saline, 40 μL). The first dose was administered 15 min after the onset of MCAo and the second dose 24 h later. Neurological behavioral tests were performed 24 and 48 h after tMCAo. Infarct volume was measured 48 h after tMCAo. Additionally, a separate cohort of rats underwent permanent MCAo (pMCAo) and received two intranasal doses of CHF6467 or vehicle, with long-term neurological outcome assessed 7 days later using the De Simoni neuroscore (n = 13-14 per group). CHF6467 levels were measured in intact brain samples from CHF6467-treated rats (n = 5) and vehicle-treated controls (n = 4). Samples were collected 2 h after the last administration. Results: CHF6467 significantly improved neurological and sensorimotor performance compared with the vehicle-treated rats. This functional effect was associated with a reduction in infarct volume that was positively correlated with neurological deficit improvement. In the pMCAo cohort, CHF6467-treated rats were more likely to achieve a favorable neurological outcome at seven days compared with the vehicle-treated animals. Intranasal CHF6467 reached the brain but showed variable and non-uniform distribution across regions. Levels were highest in the olfactory bulbs, while the cortex and striatum had lower concentrations. In vehicle-treated rats, the drug was undetectable. Conclusions: This study demonstrates the neuroprotective effects of CHF6467 against ischemic brain injury, evidenced by both functional improvement and reduction in infarct volume. Although it reaches the brain, its distribution is heterogeneous and assessed only at one time-point. Further studies should examine its longer-term distribution and underlying mechanisms.