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Organic Nanocarriers for Brain Drug Delivery
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Marlene Lúcio, Carla M. Lopes, Eduarda Fernandes, Hugo Gonẹalves, Maria Elisabete C. D. Real Oliveira
Glial cell-derived neurotrophic factor (GDNF) is a small protein which promotes the survival of many types of neurons [97]. Accordingly, ongoing studies have shown that GDNF can promote the growth, regeneration and survival of substantia nigra dopamine neurons, preventing the progression of PD when given at an early stage of the disease [83, 97]. In this regard, the liposomal formulation composed by 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), Chol and stearylamine (SA) loaded with GDNF was i.n. administered in rats. GDNF demonstrated neurotrophic and neuroprotective effects of GDNF protein in the brain of rats either in GDNF not encapsulated or in GDNF encapsulated in liposomes. However, the liposomal formulation may have the advantage of a protective effect on the protein, preventing it from degrading [98].
PI3K signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
SSCs have the capability of both self-renewal and differentiation. The decision of SSCs to self-renew or undergo differentiation is the fate-determining step and is precisely regulated by the stem cell niche factors (39). SSC self-renewal provides the basis for incessant spermatogenesis in males. GDNF is a member of the transforming growth factor-β superfamily and is reported to promote survival and differentiation of several types of neuron cells in the nervous system (40). In testis, GDNF secreted by somatic Sertoli cells (neighboring the SSCs) plays an important role in the maintenance of SSCs through their self-renewal, both in vitro and in vivo (19). Mutant mice with decreased expression of GDNF exhibited the depletion of SSC reserves, while overexpression of GDNF accumulated undifferentiated spermatogonia and did not express c-Kit, the marker for spermatogonial differentiation. GDNF-overexpressing mice often encountered testicular tumors at old age (10). The effect of GDNF is mediated through a multicomponent receptor complex, which consists of GFRα1 (GDNF family receptor–α1) and RET (transmembrane tyrosine kinase receptor). GDNF binds to Ret through Gfrα1, which functions as a glycosylphosphatidylinositol-anchored docking acceptor. The depletion of GDNF, GFRα1 or Ret results in germ cell loss and defects in SSC self-renewal (41). Subsequent studies indicated that Akt is rapidly phosphorylated on addition of GDNF to germline stem (GS) cell culture system in vitro, while the addition of an inhibitor of PI3K (LY294002) blocked GS self-renewal. Conditional activation of myristoylated Akt could also induce GS proliferation in the absence of GDNF, and on transplantation into the testes of infertile mice, these cells supported spermatogenesis and produced offsprings (18). PI3K inhibitor LY294002 blocked Akt phosphorylation in SSCs treated with GDNF, which directly indicated that GDNF utilizes the PI3K/Akt signaling to control SSCs survival and self-renewal (19), especially in view of the fact that overexpression of an activated form of Akt could mediate GDNF-independent SSC self-renewal (18).
Neurotrophic Factors
Published in Martin Berry, Ann Logan, CNS Injuries: Cellular Responses and Pharmacological Strategies, 2019
GDNF was discovered to be a neurotrophic factor for cultured developing dopaminergic mesencephalic neurons.47 GDNF can promote survival of several other types of neurons in vitro and in vivo, including injured lower motor neurons.121,122 Nigrostriatal neurons can retrogradely transport GDNF from the striatum123 and express the GDNF-specific alpha receptors.52 Others have reported that GDNF injections into the adult nigra can increase dopamine turnover, induce sprouting of lesioned nigral axons in the striatum and prevent axotomy-,124 6-OHDA- or MPP+-induced death of nigrostriatal neurons.125–127 We have found that continuously infused GDNF is more potent (a much lower ED50) and more effective (more surviving neurons) in promoting survival than BDNF. GDNF infusion also results in higher survival levels than previously reported in other studies, all of which used injection techniques (Lu, X. and Hagg, T., unpublished observations).128 When started one week after the transection, GDNF can maintain the survival of those neurons that have not yet died. This may be relevant for chronic degenerative diseases where a diagnosis often is made at a time when neurons are undergoing degeneration and a remnant of neurons is still alive. However, infusion of GDNF did not prevent reductions of TH-immunostaining in lesioned nigral neurons and induced reductions of TH-staining in normal noninjured ones (Lu, X. and Hagg, T., unpublished observations).128 Thus, when comparing the effects of neurotrophic factors in the nigrostriatal system, each of the factors appears to have a slightly different set of activities (Table 9.1). On the one hand CNTF predominantly promotes survival, GDNF promotes survival and neurite outgrowth, and NT-3 predominantly regulates expression of neurotransmitter-related enzyme. It is possible that these neurotrophic factors or their derivatives can be combined in a treatment cocktail to enhance some neuronal repair processes but not affect other processes that would lead to negative side effects.
Protective effect of compound Danshen (Salvia miltiorrhiza) dripping pills alone and in combination with carbamazepine on kainic acid-induced temporal lobe epilepsy and cognitive impairment in rats
Published in Pharmaceutical Biology, 2018
Chen Jia, Shanshan Han, Liming Wei, Xiangji Dang, Qianqian Niu, Mengyu Chen, Boqun Cao, Yuting Liu, Haisheng Jiao
GDNF is widespread in the rat and human central nervous system and is also present in the hippocampus (Schmidt-Kastner et al. 1994), which is crucial for the survival and regeneration of neurons after epilepsy seizure (Airaksinen and Saarma 2002). It has been shown that treatment with rhGDNF can inhibit KA-induced seizures and also protect neuronal cell loss in the hippocampal, amygdaloidal and thalamic regions (Martin et al. 1995). To assess the neuroprotective effect of CDDP and CBZ in a KA-induced TLE model, we further investigated the expression of the neurotrophic factor GDNF in the CA3 region of the hippocampus. We found that CDDP combined with CBZ led to an obvious increase in GDNF expression compared with the control and model groups, indicating that this combination can up-regulate the expression of GDNF. Given these findings, we suggest that inhibited apoptosis due to CDDP combined with CBZ may be partly correlated with the up-regulation of GDNF expression in the CA3 area of the hippocampus.
Decreased Expression of Glial-Derived Neurotrophic Factor Receptors in Glaucomatous Human Retinas
Published in Current Eye Research, 2022
Abhigna Akurathi, Erin A. Boese, Randy H. Kardon, Johannes Ledolter, Markus H. Kuehn, Matthew M. Harper
CNTF is a member of the neuropoietic cytokine family.5 which also includes interleukin 6, IL-11, leukemia inhibitory factor, oncostatin M, cardiotropin 1, and cardiotropin-like cytokine.6 CNTF signaling is accomplished by binding to a heterotrimeric receptor complex comprised of CNTF receptor-alpha(CNTFRα), gp130, and LIF receptor-beta.7 GDNF is a neurotrophic factor and a member of the GDNF-family of ligands (GFLs). All GLFs signal through transmembrane receptor tyrosine kinase (Ret), however, the complexes will only be activated when the GFL are first bound to GDNF-family receptor-alpha receptors (GFRα).8
Therapeutic approaches of trophic factors in animal models and in patients with spinal cord injury
Published in Growth Factors, 2020
María del Carmen Díaz-Galindo, Denisse Calderón-Vallejo, Carlos Olvera-Sandoval, J. Luis Quintanar
The GDNF was first identified as a neurotrophic factor released from glial cells by Engele, Schubert, and Bohn (1991). The GDNF promote the survival of developing neurons that newly innervate or terminate in their target peripheral tissues. This molecule constitutes a class of polypeptide growth factors that are critical for the development, maintenance and regeneration of the central and peripheral nervous system (Chang et al. 2019). Actually, GDNF subfamily consists of GDNF, neurturin, artemin and persephin, which bind to the glycosylphosphatidylinositol-anchored GFRα receptors 1–4, respectively (Trupp et al. 1998). The production of GDNF from astrocytes, oligodendrocytes, and Schwann cells has made these cells important potential points of intervention for SCI therapies (Walker and Xu 2018). As a consequence of the SCI, it is produced a dense astrocytic glial scar surrounding the lesion and the astrogliosis is presumed to be a positive regulator in limiting the spread of excitotoxic molecules, thus limiting the lesion area. However, GDNF has been shown to positively modulate astrogliosis improving the conditions of the injury (Ansorena et al. 2013). Chen et al. (2018) used a combinational approach consisting of hydrogel scaffolds containing Schwann cells which overexpressed GDNF, and were transplanted into the transected rat spinal cord. The observations included increased axonal growth of ascending fibres through the scaffold into the rostral spinal cord from lumbosacral neuron cell bodies; and increased the number of regenerating unmyelinated axons, myelinated axons, total axons, and the proportion of axons which became maturely myelinated (by the action of the stimulation of host Schwann cells). Future potential clinical trials might include transfecting the patient’s own Schwann cells to overexpress GDNF, before spinal cord transplantation of the allogenic Schwann cells.