Table 3. . Summary of descriptive characteristics of included studies – Group 3 – nervous system (n = 9).
| Study (year) country | Experimental model | Treatment (drug; conc.) | Methodology/assessments | Result summary | Ref. |
|---|---|---|---|---|---|
| Yang et al. (2007), USA | IVV: injury with 6-OHDA (adult female Sprague–Dawley rats) | bpV(phen); 3 or 10 μM (0.5 μl/h) continuous flow |
Histological assessment (labeling with fluorogold neuronal tracer); immunofluorescence; western blot | • bpV(phen) (3–10 μM) ↑ presence of neurons, ↑ the number and length of dendritic processes and ↑ tyrosine phosphorylation in the substantia nigra • bpV(phen) (3–10 μM) ↑ dopaminergic innervation in the neostriatum |
[32] |
| Nakashima et al., (2008), USA | IVV: SCI at T9 vertebra level (adult female Sprague–Dawley rats) | bpV(phen); 30–300 μM (0.5 μl/h) continuous flow |
Functional tests; histological assessment (CTB labeling); immunofluorescence | • bpV(phen) (30 and 100 μM) ↓ loss of sensory axons and white matter; the area of spared dorsal column white matter at the injury epicenter was greatest at 100 μM • bpV(phen) (100 μM) improved hindlimb grid-walking performance when compared with control • bpV(phen) (30 and 100 μM) ↑ CTB-labeled innervation of gracile nucleus and myelinated sensory axons; ↓Iba-1 and ↑ RECA-1 |
[31] |
| Walker et al., 2012, (USA) | IVV: unilateral cervical SCI (adult female Sprague–Dawley rats) | bpV(pic); 400 μg/kg – 2×/day (IP) |
Histological assessment (cresyl violet acetate staining); immunofluorescence; behavioral and functional tests; western blot | • bpV(pic) (400 μg/kg) ↓ lesion, ↓ cavity volume, ↑ number of motorneurons in the surrounding injury epicenter and ↑ RECA-1+ gray matter area (indicative of vascularization) • bpV(pic) (400 μg/kg) recovered the skilled forelimb function and coordination • bpV(pic) (400 μg/kg) did not significantly altered PTEN, but ↑p-AKT and ↓LC3II/LC3I ratio (↓ autophagic activity upregulation) |
[27] |
| Mao et al., (2013), China | IVT: PCN (from mouse embryos) IVV: Transient MCAO stroke model (adult male CD-1 mice) |
IVT: bpV(phen); 0.1 μM IVV: bpV(phen); 200 μg/kg/day (IP) |
IVT: measurement of neurite outgrowth (PCN submitted to emulated ischemic injury) IVV: neurological score and functional tests; Infarct volume assessment (TTC staining); Bielschowsky silver staining (a marker for axons, to assess axonal regrowth and density); immunohistochemistry; western blot |
• IVT: bpV(phen) (0.1 μM) ↑ neurite outgrowth after oxygen-glucose deprivation. • IVV: bpV(phen) (200 μg/kg) improved neurological scores (days 11–14) and asymmetrical motor deficits (day 13) • bpV(phen) (200 μg/kg) did not alter infarct volume (day 4) • While Bielschowsky silver staining and MBP immunoreactivity were decreased in the striatal IBZ (day 14) after treatment with saline, bpV(phen) (200 μg/kg) restored Bielschowsky silver staining and MBP to levels comparable to sham control • bpV(phen) (200 μg/kg) resulted in significant ↑p-AKT ↑p-S6 in striatal IBZ, as well as ↓PTEN expression |
[22] |
| Walker and Xu (2014), USA | IVV: unilateral cervical SCI (adult female Sprague–Dawley rats) | bpV(pic); 400 μg/kg – 2×/day (IP) |
Histological assessment (cresyl violet acetate and LFB stainings for calculation of spared myelinated tissue); immunofluorescence; assessment of penumbral motor neuron atrophy | • bpV(pic) (400 μg/kg) ↑ white matter and ↑ LFB+ myelin around injury epicenter • bpV(pic) (400 μg/kg) ↑ the number of CC1+ oligondendrocytes • bpV(pic) (400 μg/kg) ↑ the soma area of ventral horn motor neurons (and exhibited similar size and morphological appearance to the normal tissue (sham-operated group) |
[28] |
| Chen et al. (2015), China | IVV: intravascular perforation – SAH model (male Sprague–Dawley rats) | bpV(pic); 200 μg/kg – every 6 h (IP) |
Neurological score; SAH score; brain water content; Evans blue dye extravasation; TUNEL assay; Nissl staining; western blot | • No difference was reported regarding the SAH grading scores of vehicle-treated and bpV-treated groups • bpV(pic) (200 μg/kg) improved neurological scores; ↓ neuronal degeneration, ↓ TUNEL-positive neurons in the hippocampal CA1 region • bpV(pic) (200 μg/kg) significantly ↓ water content in brain (except for brain stem) and ↓ Evans blue extravasation in the right and left/ipsilateral hemispheres • bpV(pic) (200 μg/kg) significantly ↓PTEN, ↑p-PTEN, ↓GluR1, ↑GluR2 and ↑GluR3 |
[17] |
| Mao et al. (2015), China | IVV: transient MCAO (adult male Sprague–Dawley rats) | bpV†; 200 μg/kg/day (IP) |
Neurological score; infarct volume assessment; qPCR; ELISA; western blot. | • bpV† (200 μg/kg) improved neurological score and ↓ infarct volume • bpV† (200 μg/kg) ↑IL-10 and ↓ TNF-α concentrations in the IBZ; ↓PTEN (mRNA and protein levels), ↑PI3K, ↑AKT and ↑p-GSK3β in the striatal IBZ |
[23] |
| Walker et al. (2015), USA | IVV: unilateral cervical SCI (adult female Sprague–Dawley rats) | bpV(pic); 400 μg/kg – 2×/day (IP) |
Behavioral and functional tests; histological assessment (cresyl violet acetate staining); immunofluorescence | • bpV(pic) (400 μg/kg) improved recovery of sensorimotor function, ↓ lesion area, ↓cavity area, ↑ spared tissue area, promoted ventral horn neuron sparing and ↑ SMI-31+ and RECA-1+ area as a fraction of Schwann cells-graft area (indicative of axonal growth into the graft as an index of lesion size) | [29] |
| Pham and Tu (2018), Japan | IVV: Sciatic nerve axotomy (in a Type-2 diabetic C57BL/6J mice) | SF1670; 200 nM (0.11 μl/h) continuous flow |
Functional and morphological nerve regeneration tests (paw withdrawal thresholds measured with calibrated von Frey filaments and stereomicroscopy); sciatic nerve transection-regeneration model (fluoro-ruby staining) | • SF1670 (200 nM) ↑ functional recovery in both diabetic and non-diabetic mice (responded to von Frey filaments at 3 weeks, compared with no response in vehicle-treated groups) • SF1670 ↑ the number of fluoro-ruby-labeled neurons after axotomy (indicating that it may promote the axonal transport in the axon and nerve regeneration after nerve transection) |
[25] |
†
bpV compound was not specified by the authors.
↓: Decrease(d)/downregulation; ↑: Increase(d)/upregulation; BEAS2B: Transformed human lung epithelial cell line; C2C12: Mouse myoblast cell line; CTB: Cholera toxin subunit B; DRGN: Dorsal root ganglion neuron; DU147: PTEN functional prostate cancer cell line; FAK: Focal adhesion kinase; h: hour; HCE: Human corneal epithelial cell; hUAEC: Primary human upper airway epithelial cell; IBZ: Ischemic boundary zone; IκBα: Inhibitor of κB α; LFB: Luxol fast blue; LNCaP: PTEN-null prostate cancer cell line; IP: Intraperitoneal injection; IVT: In vitro; IVV: In vivo; MBP: Myelin basic protein; MCAO: Middle cerebral artery occlusion; min: minute; MSC: Muscle stem cell; OLP: Oligodendrocyte progenitor; ONL: Outer nuclear layer; p: phosphorylated; PCN: Primary cortical neuron; RD: Retinal detachment; RT-PCR: Reverse transcription polymerase chain reaction; SAH: Subarachnoid hemorrhage; SCI: Spinal cord injury; SR: Subretinal injection; TEER: Trans-epithelial electrical resistance.