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High pinocytotic activity Endoneurial microvessels: More permeable than perineurium Tight junctions between Endothelial cells in microvessels Innermost perineurial epithelioid myofibroblast cells Molecules Barrier proteins Transporters: Influx & Efflux Functions Endoneurial ionic microenvironment: Regulation Transendothelial electrical resistance (TEER): High Permeability to solutes & macromolecules: Low Transendothelial water flux (hydraulic conductivity): Low Possible Disorders AIDP CIDP HIV sensory neuropathy HIEM Adults: Sural nerve Nerve Structure Nerve (Sural): Axons Normal Large & Small axons in endoneurium Large axons: Surrounded by clear myelin halos Small axons: Clustered among large myelinated axons Neurofilament stain Toluidine blue stain Axon morphology (Adult): 3 size populations Large: Thick myelin sheath Intermediate: Thin myelin sheath Small: Unmyelinated axons Compare to: Infant Myelinated Axon From Robert E Schmidt MD Small, Unmyelinated Axons Small axons in Clusters Several are often surrounded by processes from single Schwann cell Singletons Small, unmyelinated axons: After axon loss Singletons : 1 axon/Schwann cell Nerve (Sural): Schwann cells, Non-myelinating NCAM1 stain Neural Cell Adhesion Molecule (NCAM1) NCAM is abundant in non-myelinating (Remak) Schwann cells that surround Unmyelinated axons NCAM is also present in Adaxonal Schwann cell cytoplasm around myelinated axons Myelin sheaths of some larger axons Myelinated axons : Are generally smaller than in the more proximal sciatic nerve NCAM stain Neurofilament stain (Green) NCAM stain (Red) Overlap (Yellow) NCAM in Non-myelinating Schwann cells Surrounds most small unmyelinated axons (Yellow) Not present around large, myelinated axons (Green) May occur in the center of larger axons (Yellow) See: Loss of small axons Neurofilament stain (Green) NCAM stain (Red) Overlap (Yellow) NCAM & P0 Normal: Mostly present in different endoneurial cells NCAM Non-myelinating Schwann cells (Green) Small amounts in non-compacted areas of myelinating Schwann cell cytoplasm (Yellow) P0: Myelin & Myelinating Schwann cell cytoplasm (Red) Schwann Cell Pathology Bngner bands: NCAM & P0 present in same Schwann cells Onion bulbs NCAM stain (Green) p0 stain (Red) NCAM & MBP Normal: Mostly present in different endoneurial cells NCAM Non-myelinating Schwann cells (Green) Small amounts in non-compacted areas of myelinating Schwann cell cytoplasm (Yellow) MBP: In Myelin surrounding larger axons (Red) NCAM stain (Green) MBP stain (Red) Epineurial vessels & Supporting cells in endoneurium ATPase pH 4.3 stain Epineurial Vessels VvG stain Epineurial vessels: Normal Artery (Black arrow): Linear fibrils near lumen

Acute subjective effects (improved focus, verbal fluency) are reported within 24 hours post-dose in some users, but structural synaptogenesis the mechanism underlying long-term cognitive enhancement requires 24 weeks of consistent dosing to produce measurable changes in memory or learning tasks