Traumatic brain injury and recovery mechanisms: peptide modulation of periventricular neurogenic regions by the choroid plexus-CSF nexus

Abstract

In traumatic brain injury (TBI), severe disruptions occur in the choroid plexus (CP)-cerebrospinal fluid (CSF) nexus that destabilize the nearby hippocampal and subventricular neurogenic regions. Following invasive and non-invasive injuries to cortex, several adverse sequelae harm the brain interior: (i) structural damage to CP epithelium that opens the blood-CSF barrier (BCSFB) to protein, (ii) altered CSF dynamics and intracranial pressure (ICP), (iii) augmentation of leukocyte traffic across CP into the CSF-brain, (iv) reduction in CSF sink action and clearance of debris from ventricles, and (v) less efficient provision of micronutritional and hormonal support for the CNS. However, gradual post-TBI restitution of the injured CP epithelium and ependyma, and CSF homeostatic mechanisms, help to restore subventricular/subgranular neurogenesis and the cognitive abilities diminished by CNS damage. Recovery from TBI is facilitated by upregulated choroidal/ependymal growth factors and neurotrophins, and their secretion into ventricular CSF. There, by an endocrine-like mechanism, CSF bulk flow convects the neuropeptides to target cells in injured cortex for aiding repair processes; and to neurogenic niches for enhancing conversion of stem cells to new neurons. In the recovery from TBI and associated ischemia, the modulating neuropeptides include FGF2, EGF, VEGF, NGF, IGF, GDNF, BDNF, and PACAP. Homeostatic correction of TBI-induced neuropathology can be accelerated or amplified by exogenously boosting the CSF concentration of these growth factors and neurotrophins. Such intraventricular supplementation via the CSF route promotes neural restoration through enhanced neurogenesis, angiogenesis, and neuroprotective effects. CSF translational research presents opportunities that involve CP and ependymal manipulations to expedite recovery from TBI.

Fig. 1

Anatomical relationships among the BCSFB, CSF, and BBB: neurons receive supplies from two sources: the nearby cerebral capillaries or BBB (mainly glucose, amino acids and free fatty acids) and the more distant CP or BCSFB (mainly vitamins, growth factors, neurotrophins, and hormones). Both the BBB and BCSFB reabsorb neural waste products and unneeded proteins into blood. The brain microvessel endothelium and CP epithelium both have tight junctions that restrict diffusion of small water-soluble molecules: therefore ion and organic solutes are actively transported via membrane carriers (structural proteins) across the barriers. Ependyma is a single-cell epithelial layer with highly permeable gap junctions that allows free exchange of solutes paracellularly between brain ISF and ventricular CSF

Fig. 2

Central role of CP–CSF in exchanging materials with brain: ions, water, and organic molecules filter passively out of choroidal capillaries (arrow #1) into interstitial fluid (ISF). This is the first step in the material flow by distributional nexus to the brain (green arrows). Solutes diffuse through ISF up to basolateral membrane of epithelium. Active mechanisms in membranes transfer solutes sequentially across the basolateral (#2) and apical membranes (#3), into ventricular CSF. As CSF flows (#4) from ventricles to cisterna magna, a small fraction of the CSF-borne substances diffuse across ependyma (#5) into periventricular brain or are taken up by specialized ependymal cells. Ependyma-penetrating substances diffuse through brain ISF (#6) for transport into neurons (N); BBB, not depicted, is interspersed among neurons. Material inflow to the CNS interior thus sequentially involves CP, CSF, ependyma and brain. In the opposite direction, there is a reverse nexus (red arrows) for catabolites or injury products (as in TBI) released by neurons/glia into brain ISF. Accordingly, cerebral catabolites such as homovanillic acid diffuse through ISF (arrow #7), and down a transependymal concentration gradient into CSF (#8). By bulk flow of CSF (#9), catabolites are convected to subarachnoid space (not depicted) or to CP for active removal from the ventricles (#10), and then extrusion transport across basolateral membrane (#11). Therefore, some endogenous solutes or injury products end up being cleared passively into blood of microvessels (#12) and venules draining CP. Overall CSF is simultaneously a source (#1 to #6) and a sink (#7 to #12) for distributing molecules, depending on prevailing concentration gradients between ventricular CSF and brain ISF. As such, the CSF and bordering cells constitute a nexus for mediating trophic (CSF to brain) and excretory (brain to CSF) fluxes

Fig. 3

Dilated intercellular spaces in choroid plexus after blast injury: rat choroidal epithelium 7 days post-blast reveals dilated clefts or intercellular spaces (IS). The single blast condition is described in text. Microvilli (MV) are dilated. Ventricular lumen contains pedunculated cytoplasmic protrusions released from epithelium(asterisks). Basal lamina is demarcated by arrowheads. Scale bar is 2 μm. Reprinted from Kaur et al.

Fig. 4

Neighboring epithelial cells in choroid plexus with and without damage: electron micrograph shows adjacent epithelium in rat CP 14 days after a single blast injury. Cell on left has a great number of hydropic vacuoles, likely reflecting enhanced activity of lysosomes (Johanson et al. 2010b) processing/digesting debris generated from injury. Microvilli in injured cell are more dilated than counterparts in the relatively intact epithelial cell on right. Basal lamina is indicated by arrows. Tight junctions are encircled. Scale bar is 1.5 μm. Reprinted from Kaur et al.

Fig. 5

Enhanced permeability of BCSFB after TBI in adult rat: Breakdown of CP epithelial barrier was evaluated by rapid uptake (over 5 min) of radioiodine in plasma into CSF (sampled from cisterna magna). At 5 h of TBI, the permeability to ¹³¹I increased significantly by 7-fold, compared to non-lesioned controls (P < 0.01, ANOVA followed by Dunnet’s test). Bars are means + SD for 5 animals. Permeability change was blunted if Cerebrolysin (CERE), a mixture of growth factors and trophic peptides, was administered 1 h (P < 0.05) but not at 2 h post-induction of stab wound to parietal cortex (see Table 1). CONT control (sham surgery, no lesioning)

Fig. 6

TBI damage to CP: micrograph shows damage to CP in the right lateral ventricle 5 h after stab injury to the ipsilateral cerebral cortex (parietal) in the rat. The choroidal epithelium appears shrunken. Disruption to the epithelial cells manifests as the uptake of serum albumin (brown reaction product). This indicates damage to the normally restrictive BCSFB (Johanson and Sharma, unpublished observation)

Fig. 7

TBI damage to ependyma/periventricular regions: Image shows damage to periventricular ependymal cells in the third ventricle and the surrounding neuropil 5 h after TBI in the right parietal cortex of the rat. Uptake of albumin marker (from plasma) is seen as the brown reaction product visible in the ependymal lining. Also vacuolation, edema, and sponginess around the periventricular neuropil are apparent. In the neuropil, the albumin-labeled neurons reflect widespread disruption of the BBB (and indirectly, the BCSFB) after TBI to cerebral cortex (Johanson and Sharma, unpublished observation)