Table 4.
Anti-inflammatory effect of GDNF in preclinical trials of Parkinson’s disease and other neurological diseases.
| Experimental Model/GDNF Therapeutic Approach | GDNF Relevant Effects | Proposed Mechanisms | Ref. |
|---|---|---|---|
| (a) Neurodegenerative disease | |||
| Parkinson’s disease | |||
| Midbrain microglial cultures activated by Zymosan A/Therapy with astrocyte-derived GDNF. | GDNF decreases microglial activation in a model of neuroinflammation in vitro. | Activation of the GFRα1-RET complex and inhibition of the FAK pathway. | [33] |
| 12-month-old GDNF+/- knockdown mice/Bilateral intrastriatal injection of GDNF (10 μg per hemisphere). | Attenuation of motor impairments and nigrostriatal dopamine levels. | Reduction of the COX-2 expression and increase in SOD-2 levels in the SN suggests reduced microglial activation. | [32] |
| Rat microglial culture activated by LPS/Therapy with rHGDNF (50 ng/mL, before LPS administration). | Prevention of NO synthesis and iNOS COX-2, IL-6, IL-1β, and TNF-α expression. | Inhibition of microglial activation by reducing phosphorylation of p38 *. | [31] |
| 6-OHDA-induced PD rat model/Intrastriatal GDNF released by LCM (1.5 mg/kg, 3d after 6-OHDA injection). | Reduction of caspase-3 and TNF-α levels and activation of microglia. | Reduced microglial activation by lowering MMP-9 and MHC II expression, which consequently retains DA. | [30] |
| Intracutaneous 6-OHDA injection in mice/GDNF transfected macrophages (i.v. 1 × 106 cells/100 μL, 2d after 6-OHDA). | It decreased activated microglia in SNpc. | The macrophages migrate to inflammation sites and provide neuroprotection modulating glial cells activation. | [27] |
| Intraperitoneal MPTP injection in mouse/IN GDNF delivery by peptide-conjugated lipid nanocarriers (2.5 μg, 2.5 μL per nostril, 4 sessions). | It decreased activated microglia. | It targets microglia activation, modulating the neuroinflammation. | [28] |
| Transgenic Parkin Q311X(A) mice (4-month-old)/Administration of GDNF-macrophages (i.v. 2 × 106 cells/100 μL/mouse, once a wk for 3wk). | Disminution of microgliosis and astrogliosis. | Anti-neuroinflammatory effect by modulating glial activation. | [27] |
| Intraperitoneal MPTP injection in mouse twice a wk for 3wk/GDNF gene delivery via the UTMD system (3.6 × 108 MBs/mL, twice a wk for 3wk, 1d after MPTP). | It decreased apoptosis and astrogliosis. | Reduced expression of calcium ions and the apoptotic protein caspase 3. | [26] |
| Alzheimer’s disease | |||
| Murine microglial cell line BV2 stimulated with Aβ-protein/GDNF (100 and 500 ng/mL, after Aβ-protein administration). | Decreased levels of TNF-α, TGF-β, IL-1β, and IL-12β, in a dose-dependent manner. | Inhibition of microglial activation by reducing YAP phosphorylation (Hippo/YAP pathway). | [175] |
| Amyotrophic lateral sclerosis | |||
| Transgenic SOD1G93A rat (90d old)/i.m. grafts of hMSC-GDNF (150,000 cells in 50 μL, at 24h, 1 and 2wk). | Reduced inflammation markers and promoted TSC survival. Delayed onset of ALS symptom | Delayed ALS symptom onset by preserving NMJ integrity. | [176] |
| Multiple sclerosis | |||
| CEAE animal model for multiple sclerosis: Transplantation of GDNF/NSCs in each lateral ventricle (5 × 105 in 10 μL, 10d after the CEAE induction). | Reduced inflammatory infiltrates in the STR and the astrocyte differentiation of NSCs. | Possible activation of myeloid dendritic cells and subsequent restriction T cell expansions. | [177] |
| (b) Other neurological diseases | |||
| Murine microglial cell line BV2 with ADSCs-GDNF (500 ng/L). | Inhibition of the M1 phenotype and promoting the M2 phenotype. | Microglial activation and polarization via PI3K/AKT signaling pathway. | [179] |
| Neuropathic pain model by CCI in rats/rAV-GDNF [2 × 109 pfu/100 mL PBS] injection in the triceps brachii muscle. | Down-regulated protein expression of MMP9, p38, IL6, IL1β, and iNOS. | Inhibition of microglial activation and cytokine production via p38 and PKC signaling. | [180] |
| FCI rat animal model and neuronal culture GOSD/NCM with TGFβ1, GDNF, and NT-3 (1 ng/mL for each brain cell in plates; 6.4 × 106/plate) and incubated under GOSD conditions (2 h). | Reduction of the brain infarction and motor deficit. | Anti-apoptotic, anti-oxidant, and potentially anti-glutamate activities. | [181] |
| (c) Systemic diseases | |||
| UUO mice model/GDNF-AMSCs (i.v. 150 μl cell of suspension containing 5 × 105 cells via the tail vein). | Activation of M2 macrophages and reduced renal fibrosis by suppressing inflammation. | Down-regulated TNF-α and iNOS; upregulated IL-4 and IL10. | [182] |
| Experimental colitis mouse model induced by DSS/rAV-GDNF ( intracolonically 1 × 1010 pfu/mouse) | Reduction in enhanced permeability by restoring epithelial barrier function. | Inhibition of TNF-α, IL-1β, MPO, caspase-3, and NF-kB. Increase in ZO-1 and AKT. | [183] |
Abbreviations: 6-OHDA, 6-hidroxydopamine; ADSCs, adipose-derived stem cells; AKT, serine-threonine protein kinase; ALS, Amyotrophic lateral sclerosis; AMSCs, adipose-derived mesenchymal stem cells; Aβ, Amyloid beta; CCI, chronic constriction injury; CEAE, Chronic Experimental Allergic Encephalomyelitis; COX-2, Cyclooxygenase-2; DA, dopamine; DSS, dextran sulphate sodium; FAK, Focal adhesion kinase pathway; FCI, Focal cerebral ischemia; GDNF, Glial cell line-derived neurotrophic factor; GFRα, GDNF family receptor alpha; GOSD, Glucose-Oxygen-Serum-Deprivation; hMSC, Human mesenchymal stem cell; i.m., intramuscular; i.p., intraperitoneal; i.v., intravenous; IL, Interleukin; IN, intranasal; iNOS, inducible nitric oxide synthase; LCM, lipid-coated microbubbles; LPS, Lipopolysaccharide;MBs, microbubbles; MHC-II, major histocompatibility complex; MMP, Matrix metalloproteinase; MPO, Myeloperoxidase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NCM, neuron-derived conditioned medium; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NMJ, neuromuscular junction; NO, nitric oxide; NSCs, Neural Stem Cells; NT-3, neurotrophin-3; p38, Mitogen activated protein kinase p38; PBS, phosphate buffer saline; PD, Parkinson’s disease; pfu, plaque-forming units; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; rAV, recombinant adenovirus; RET, Receptor tyrosine-protein kinase; rhGDNF, recombinat human GDNF; SN, Substantia nigra; SNpc, Substantia nigra pars compacta; SOD, superoxide dismutase; STR, striatum; TGF-β, Transforming growth factor-β; TNF-α, Tumor necrosis factor-α; TSC, Terminal Schwann cell; UTMD, ultrasound-targeted microbubble destruction; UUO, unilateral ureteral obstruction; YAP, yes-associated protein; ZO-1, Zonula occludens-1. * p38, mitogen-activated protein kinases, p38/MAPK pathway.