Enhancing Plasticity of the Central Nervous System: Drugs, Stem Cell Therapy, and Neuro-Implants

Abstract

Stroke represents the first cause of adult acquired disability. Spontaneous recovery, dependent on endogenous neurogenesis, allows for limited recovery in 50% of patients who remain functionally dependent despite physiotherapy. Here, we propose a review of novel drug therapies with strong potential in the clinic. We will also discuss new avenues of stem cell therapy in patients with a cerebral lesion. A promising future for the development of efficient drugs to enhance functional recovery after stroke seems evident. These drugs will have to prove their efficacy also in severely affected patients. The efficacy of stem cell engraftment has been demonstrated but will have to prove its potential in restoring tissue function for the massive brain lesions that are most debilitating. New answers may lay in biomaterials, a steadily growing field. Biomaterials should ideally resemble lesioned brain structures in architecture and must be proven to increase functional reconnections within host tissue before clinical testing.

Figure 1

Neuro-implant concept. Guiding scaffolds located in the lesion of the corticospinal tract may improve tissue reconstruction and appropriate direction of regenerated tracts.

Figure 2

Representative horizontal brain section of the lesioned area of rats with implants alone (a) (scale bar: 1 mm) and neuro-implants (b) under brightfield illumination. The newly generated tissue was mostly located around the PDMS implants. (b) Human neural stem cells were identified by a specific human marker hNCAM or hMTCO2, in combination with a marker (in green) of immature (nestin) and mature (MAP2) neurons. Low magnification is provided on the left and higher magnifications on the right (scale bars: 100 μm). Grafted cell neurites were aligned along the grooves of the implant.

Figure 3

Measurement of cerebral blood flow by nanoSPECT Plus-CT Bioscan with [^99mTc]-HMPAO. Fifteen minutes after intravenous injection of 50 MBq of [^99mTc]-HMPAO in the tail vein of Sprague-Dawley anesthetized rats, data were acquired during 7 min for SPECT (48 sec and 100000 cps per projection, image size 276 × 276 × 164, 0.1 mm) and 1 min for CT (55 kVp, 500 msec, pitch 0.5, binning 1 : 4). Following the reconstruction, the CT images were spatially aligned to match the SPECT images. Processing of reconstructed images was performed with the in-house Sysiphe software [79]. Brain implants were identified on CT (blue arrows), and 3D volumes of interest (VOIs) were drawn on either side of the implants (colored rectangles) and symmetric ROIs were drawn on the contralateral side as a control (not shown). Images of two rats 20 days after a corticostriatal lesion and 7 days after implantation of neuro-implants. (a, e) CT scan of the brain implants (blue arrows). One implant was inserted in rat number 1 brain and 5 implants in rat number 2 brain. (b, f) SPECT-CT with HMPAO radiotracer on the area of the brain implant. (c, g) SPECT-CT with HMPAO radiotracer on the area of brain damage (located behind the implantation zone). We observed major hypoperfusion (red arrow). The presence of implants limited the hypoperfusion: for rat number 1, −13% in (b) compared to −25% in (c) (ROI volume was 0.4 mm³) and for rat number 2, −18% in (f) compared to −57% in (g) (ROI volume was 1.5 mm³). (h) Sagittal view of rat number 1. Coronal views (b, c) are located with grey and red lines. (d, i) Rat brain perfused and extracted 3 months after the lesion showing the lesion area where neuro-implants were inserted (grey arrows) or not (red arrows).