The small molecule FKBP ligand GPI 1046 induces partial striatal re-innervation after intranigral 6-hydroxydopamine lesion in rats

Ross, Douglas T.; Guo, Hongzhi; Howorth, P. J. N.; Chen, Yi; Hamilton, Gregory S.; Steiner, Joseph P.

doi:10.1016/s0304-3940(00)01683-9

Cited by 32 publications

(16 citation statements)

References 16 publications

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“…However, in contrast to neurotrophins, most immunophilin ligands are highly stable and can readily cross the blood-brain barrier, prompted the development of nonimmunosuppressive immunophilin ligands with potent and selective therapeutic activities. GPI-1046, one of nonimmunosuppressive immunophilin ligands, binds to FKBP12, and like FK506, it showed neuroprotective and neuroregenerative effects on primary cultures of midbrain dopaminergic neurons against both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) toxicities [55] , while exerting similar effects in rodent models [56,57] . GPI-1485, the second-generation compound of GPI-1046, demonstrated substantial efficacy in preclinical and initial phases of clinical evaluation for Parkinson's disease (PD) model [58] .…”

Section: Role Of Fkbps In Neuronal Cellsmentioning

confidence: 99%

FKBP Family Proteins: Immunophilins with Versatile Biological Functions

Hong²,

et al. 2008

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Immunophilins consist of a family of highly conserved proteins binding with immunosuppressive drugs such as FK506, rapamycin and cyclosporin A. FK506-binding protein (FKBP) is one of two major immunophilins and most of FKBP family members bind FK506 and show peptidylprolyl cis/trans isomerase (PPIase) activity. Small size FKBP family members contain only FK506-binding domain, while FKBPs with large molecular weights possess extra domains such as tetratricopeptide repeat domains, calmodulin binding and transmembrane motifs. FKBPs are involved in several biochemical processes including protein folding, receptor signaling, protein trafficking and transcription. FKBP family proteins play important functional roles in the T-cell activation, when complexed with their ligands. The roles of immunophilins in protein transportation and apoptosis through their molecular interactions with receptors or proteins have emerged recently. Moreover, therapeutic implications of immunophilin ligands in treating neurodegenerative disorders have been accumulating. FK506 and its derivatives with no immunosuppressive activities bind to the conserved active sites of the canonical FKBP members such as FKBP12, which shows PPIase activity. These immunophilin ligands show variable efficacy in animal models for Parkinson’s disease, dementia, and spinal cord injury, where the canonical immunophilins function as chaperones and are associate with the protein folding and modulation of oxidative stress. On the other hand, in the noncanonical FKBP members such as FKBP38, FK506-binding site is not conserved and shows neither PPIase activity nor affinity to FK506. Interestingly, the small molecule-mediated inhibition of the noncanonical member of FKBP family appears to cause neuronal protection and induce proliferation of neuronal stem cells in a rat focal cerebral ischemia model. Currently, the mechanisms of actions remain unclear. This review focuses on molecular characteristics of the canonical and noncanonical FKBP family members and the biological functions of their ligands in performing neuroprotective and neurotrophic activities.

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Section: Role Of Fkbps In Neuronal Cellsmentioning

confidence: 99%

FKBP Family Proteins: Immunophilins with Versatile Biological Functions

Hong²,

et al. 2008

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“…Several studies report that FK506 and related non-immunosuppressive immunophilin ligands, such as GPI-1046 and V10367, have neurotrophic/ neuroprotective effects on dopaminergic neurons following MPTPor 6-OHDA-induced lesion (Steiner et al, 1997;Costantini et al, 1998Costantini et al, , 2001Ross et al, 2001;Zhang et al, 2001a;Tanaka et al, 2002a). Neurotrophic effects to dopaminergic neurons are also observed in vitro (Costantini and Isacson, 2000;Guo et al, 2001).…”

Section: Immunophilin Ligandsmentioning

confidence: 99%

Driving GDNF expression: The green and the red traffic lights

Saavedra

Baltazar

Duarte

2008

Progress in Neurobiology

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“…These compounds represent a relatively new class of drugs with demonstrated effectiveness in animal models of PD. [88][89][90] Tanaka and associates 91 have evaluated the ability of immunosoppressive (FK506) and non-immunosoppressive (GPI1046) drugs to activate neurotrophic factors such as BDNF and GDNF. Whereas, both compounds were able to enhance GDNF expression, only the immunosoppressive molecule induced striatal expression of BDNF.…”

Section: Nicotinementioning

confidence: 99%

Shedding light into the role of BDNF in the pharmacotherapy of Parkinson's disease

Fumagalli¹,

Racagni

Riva³

2006

Pharmacogenomics J

119

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Parkinson's disease (PD) is a chronic, neurodegenerative disease with a 1% incidence in the population over 55 years of age. Movement impairments represent undoubtedly the hallmark of the disorder; however, extensive evidence implicates cognitive deficits as concomitant peculiar features. Brainderived neurotrophic factor (BDNF) colocalizes with dopamine neurons in the substantia nigra, where dopaminergic cell bodies are located, and it has recently garnered attention as a molecule crucial for cognition, a function that is also compromised in PD patients. Thus, due to its colocalization with dopaminergic neurons and its role in cognition, BDNF might possess a dual role in PD, both as a neuroprotective molecule, since its inhibition leads to loss of nigral dopaminergic neurons, and as a neuromodulator, as its enhanced expression ameliorates cognitive processes. In this review, we discuss the mechanism of action of established as well as novel drugs for PD with a particular emphasis to those interfering with BDNF biosynthesis.

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The small molecule FKBP ligand GPI 1046 induces partial striatal re-innervation after intranigral 6-hydroxydopamine lesion in rats

Cited by 32 publications

References 16 publications

FKBP Family Proteins: Immunophilins with Versatile Biological Functions

FKBP Family Proteins: Immunophilins with Versatile Biological Functions

Driving GDNF expression: The green and the red traffic lights

Shedding light into the role of BDNF in the pharmacotherapy of Parkinson's disease

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