Glial Cell Line-Derived Neurotrophic Factor Family Ligands, Players at the Interface of Neuroinflammation and Neuroprotection : Focus Onto the Glia

Well-known effects of neurotrophic factors are related to supporting the survival and functioning of various neuronal populations in the body. However, these proteins seem to also play less well-documented roles in glial cells, thus, influencing neuroinflammation. This article summarizes available data on the effects of glial cell line derived neurotrophic factor (GDNF) family ligands (GFLs), proteins providing trophic support to dopaminergic, sensory, motor and many other neuronal populations, in non-neuronal cells contributing to the development and maintenance of neuropathic pain. The paper also contains our own limited data describing the effects of small molecules targeting GFL receptors on the expression of the satellite glial marker IBA1 in dorsal root ganglia of rats with surgery- and diabetes-induced neuropathy. In our experiments activation of GFLs receptors with either GFLs or small molecule agonists downregulated the expression of IBA1 in this tissue of experimental animals. While it can be a secondary effect due to a supportive role of GFLs in neuronal cells, growing body of evidence indicates that GFL receptors are expressed in glial and peripheral immune system cells. Thus, targeting GFL receptors with either proteins or small molecules may directly suppress the activation of glial and immune system cells and, therefore, reduce neuroinflammation. As neuroinflammation is considered to be an important contributor to the process of neurodegeneration these data further support research efforts to modulate the activity of GFL receptors in order to develop disease-modifying treatments for neurodegenerative disorders and neuropathic pain that target both neuronal and glial cells.Peer reviewe

A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo

Parkinson’s disease (PD) is the most common age-related movement disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons. To date, PD treatment strategies are mostly based on dopamine replacement medicines, which can alleviate motor symptoms but do not slow down the progression of neurodegeneration. Thus, there is a need for disease-modifying PD therapies. The aim of this work was to evaluate the neuroprotective effects of the novel compound PA96 on dopamine neurons in vivo and in vitro, assess its ability to alleviate motor deficits in MPTP- and haloperidol-based PD models, as well as PK profile and BBB penetration. PA96 was synthesized from (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl) cyclohex-3-ene-1,2-diol (Prottremin) using the original three-step stereoselective procedure. We found that PA96: (1) supported the survival of cultured näive dopamine neurons; (2) supported the survival of MPP+-challenged dopamine neurons in vitro and in vivo; (3) had chemically appropriate properties (synthesis, solubility, etc.); (4) alleviated motor deficits in MPTP- and haloperidol-based models of PD; (5) penetrated the blood–brain barrier in vivo; and (6) was eliminated from the bloodstream relative rapidly. In conclusion, the present article demonstrates the identification of PA96 as a lead compound for the future development of this compound into a clinically used drug

Biological activity In vitro, absorption, BBB penetration and tolerability of nanoformulation of BT44, a RET agonist with disease-modifying potential for the treatment of neurodegeneration

BT44 is a novel, second generation glial cell line-derived neurotropic factor (GDNF) mimetic, with improved biological activity and a lead compound for the treatment of neurodegenerative disorders. Like many other small molecules, it suffers from intrinsic poor aqueous solubility, posing significant hurdles at various levels for its preclinical development and clinical translation. Herein, we report a poly(2-oxazoline)s (POx) based BT44 micellar nanoformulation with ultra-high drug loading capacity of 47 wt.%. The BT44 nanoformulation was comprehensively characterized by 1H-NMR spectroscopy, differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), dynamic light scattering (DLS) and cryo-transmission/scanning electron microscopy (cryo-TEM/SEM). The DSC, XRD and redispersion studies collectively confirmed that the BT44 formulation can be stored as a lyophilized powder and can be redispersed upon need. The DLS suggested that the redispersed formulation is suitable for parenteral administration (Dh ≈ 70 nm). The cryo-TEM measurements showed the presence of worm-like structures both in plain polymer and BT44 formulation. The BT44 formulation retained biological activity in immortalized cells and in cultured dopamine neurons. The micellar nanoformulation of BT44 exhibited improved absorption (after subcutaneous injection) and blood-brain barrier (BBB) penetration and no acute toxic effects in mice were observed. In conclusion, herein, we have developed an ultra-high BT44 loaded aqueous injectable nanoformulation, which can be used to pave way for its preclinical and clinical development for the management of neurodegenerative disorders

A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo

Parkinson's disease (PD) is the most common age-related movement disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons. To date, PD treatment strategies are mostly based on dopamine replacement medicines, which can alleviate motor symptoms but do not slow down the progression of neurodegeneration. Thus, there is a need for disease-modifying PD therapies. The aim of this work was to evaluate the neuroprotective effects of the novel compound PA96 on dopamine neurons in vivo and in vitro, assess its ability to alleviate motor deficits in MPTP- and haloperidol-based PD models, as well as PK profile and BBB penetration. PA96 was synthesized from (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl) cyclohex-3-ene-1,2-diol (Prottremin) using the original three-step stereoselective procedure. We found that PA96: (1) supported the survival of cultured naive dopamine neurons; (2) supported the survival of MPP+-challenged dopamine neurons in vitro and in vivo; (3) had chemically appropriate properties (synthesis, solubility, etc.); (4) alleviated motor deficits in MPTP- and haloperidol-based models of PD; (5) penetrated the blood-brain barrier in vivo; and (6) was eliminated from the bloodstream relative rapidly. In conclusion, the present article demonstrates the identification of PA96 as a lead compound for the future development of this compound into a clinically used drug.Peer reviewe