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Simple Summary  Central nervous system (CNS) diseases, including tumors such as glioblastomas and neurodegenerative diseases, such as Alzheimer’s disease, are some of the greatest challenges of modern medicine. Therefore, our study aimed to evaluate the anticancer and neuroprotective activity of the extract from a common European lichen  Hypogymnia physodes  and of its compound-physodic acid. The examined substances were cytotoxic against the glioblastoma cell lines A-172, T98G, and U-138 MG. Both substances strongly inhibited hyaluronidase, and diminished cyclooxygenase-2 activity ( H. physodes  extract), enzymes expressed in patients with malignant glioma. Furthermore,  H. physodes  extract inhibited tyrosinase activity, the enzyme linked to neurodegenerative diseases. The tested substances exhibited antioxidant activity, however, acetylcholinesterase and butyrylcholinesterase inhibitory activity were not high. We proved that physodic acid can cross the blood–brain barrier. We conclude that physodic acid and  H. physodes  extract should be regarded as promising agents with anticancer, chemopreventive, and neuroprotective activities, especially concerning CNS.Abstract  Lichen secondary metabolites are characterized by huge pharmacological potential. Our research focused on assessing the anticancer and neuroprotective activity of  Hypogymnia physodes  acetone extract (HP extract) and physodic acid, its major component. The antitumor properties were evaluated by cytotoxicity analysis using A-172, T98G, and U-138 MG glioblastoma cell lines and by hyaluronidase and cyclooxygenase-2 (COX-2) inhibition. The neuroprotective potential was examined using COX-2, tyrosinase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) activity tests. Moreover, the antioxidant potential of the tested substances was examined, and the chemical composition of the extract was analyzed. For physodic acid, the permeability through the blood–brain barrier using Parallel Artificial Membrane Permeability Assay for the Blood–Brain Barrier assay (PAMPA-BBB) was assessed. Our study shows that the tested substances strongly inhibited glioblastoma cell proliferation and hyaluronidase activity. Besides, HP extract diminished COX-2 and tyrosinase activity. However, the AChE and BChE inhibitory activity of HP extract and physodic acid were mild. The examined substances exhibited strong antioxidant activity. Importantly, we proved that physodic acid crosses the blood–brain barrier. We conclude that physodic acid and  H. physodes  should be regarded as promising agents with anticancer, chemopreventive, and neuroprotective activities, especially regarding the central nervous system diseases.

cancers

Permeability of Hypogymnia physodes Extract Component—Physodic Acid through the Blood–Brain Barrier as an Important Argument for Its Anticancer and Neuroprotective Activity within the Central Nervous System