Anti‐Neuroinflammatory and Neuroprotective Effects of Caffeic Acid in Experimental Models of Neurodegeneration: A Systematic Review and Meta‐Analysis

Caffeic acid, a naturally occurring polyphenol found in various dietary sources, has gained considerable interest for its antioxidant, anti‐inflammatory, and neuroprotective properties. Preclinical studies suggest that caffeic acid may exert beneficial effects in models of Alzheimer's disease, Parkinson's disease, cerebral ischaemia, ageing, diabetes‐associated cognitive decline, and neuroinflammation. To assess the neuroprotective activity of caffeic acid in neurodegenerative diseases. After performing a detailed literature search across various databases, such as Google Scholar, Embase, PubMed, Scopus, and Cochrane, a total of 44 unique studies were identified based on the framed eligibility criteria. This meta‐analysis demonstrated that caffeic acid exerts significant effect on neurobiomarker panel: amyloid‐β accumulation (IV: −1.84 [−3.08, −0.61], 95% CI, p = 0.004, I 2 = 8%), GFAP (IV: −2.03 [−2.91, −1.15], 95% CI, p < 0.00001,), AchE (IV: −1.98 [−3.44, −0.52], 95% CI, p = 0.008, I 2 = 85%), BDNF (IV: 1.14 [0.20, 2.09], 95% CI, p = 0.02, I 2 = 57%); Oxidative stress markers such as MDA (IV: −4.60 [−6.66, −2.55], 95%CI, p < 0.0001, I 2 = 99%) and LPO (IV: −2.12 [−3.49, −0.75], 95% CI, p = 0.002, I 2 = 98%), SOD (IV: 4.90 [3.72, 6.08], 95% CI, p < 0.00001, I 2 = 99%), CAT (IV: 21.35 [12.10, 30.61], 95% CI, p < 0.00001, I 2 = 94%), GSH (IV: 6.86 [5.28, 8.44], 95% CI, p < 0.00001, I 2 = 99%); Neuroinflammatory parameters including TNF‐α (IV: −4.23 [−5.89, −2.57], 95% CI, p < 0.00001, I 2 = 83%), IL‐6 (IV: −3.07 [−4.69, −1.45], 95% CI, p = 0.0002, I 2 = 78%) and IL‐1β (IV: −5.09 [−8.12, −2.07], 95% CI, p = 0.0010, I 2 = 61%); Behavioural parameters like forced swim test (IV: −2.22 [−3.83, −0.61], 95% CI, p = 0.007, I 2 = 86%), open field test‐ number of rearing's (IV: 12.50 [0.55, 24.45], 95% CI, p = 0.04, I 2 = 89%), elevated plus maze test‐ time spent in open arms (IV: −30.45 [−53.67, −7.22], 95% CI, p = 0.01, I 2 = 81%); Apoptosis (Caspase‐3) parameters (IV: −28.46 [−52.22, −4.70], 95% CI, p = 0.02, I 2 = 95%). Caffeic acid showed significant neuroprotective activity in neurodegenerative diseases based on pre‐clinical evidence, making it a promising molecule for future RCTs.