Neuroprotective potential of phloroglucinol in focal cerebral ischemia in rats: a mechanistic study

Ischemic stroke remains a leading cause of mortality and disability worldwide, with limited therapeutic options that effectively target its complex pathophysiology. This study evaluates the neuroprotective potential of phloroglucinol (PH), a polyphenolic compound with known antioxidant and anti-inflammatory properties, in a rat model of focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO). Animals were randomly assigned to different groups. Phloroglucinol was administered intraperitoneally at doses of 15 and 30 mg/kg, beginning immediately after a 1-hour MCAO injury and continuing once daily for 21 days. Treatment with phloroglucinol significantly improved neurological deficit, muscle strength, locomotor activity, and cognitive performance (Morris Water Maze (MWM) and Novel Object Recognition Test (NORT) conducted at the last week of study) compared to untreated MCAO rats. Biochemical analyses revealed that phloroglucinol reduced oxidative stress markers (malondialdehyde (MDA), nitrite), restored antioxidant defenses (glutathione (GSH) and catalase, and attenuated neuroinflammation by lowering interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels. Additionally, phloroglucinol decreased cerebral infarct volume and preserved blood-brain barrier (BBB) integrity. However, it also improved the mitochondrial functions by increasing the gene expression of hypoxia-inducing factor 1 alpha (HIF-1α) and Transcription factor A, mitochondrial (TFAM), reducing caspase-3 activation and inducing nitric oxide synthase (iNOS) gene expression, and enhancing nuclear factor erythroid 2-related factor 2/ Heme oxygenase-1 (Nrf-2/HO-1) expression. Molecular docking studies suggested that phloroglucinol may exert its effects via interaction with the Kelch-like ECH-associated protein 1 (KEAP1)-Nrf-2 pathway. These findings highlight phloroglucinol as a promising multi-target neuro-protective agent for ischemic stroke, warranting further investigation for clinical translation.