Safety, Tolerability, and Cerebrospinal Fluid Penetration of Ursodeoxycholic Acid in Patients With Amyotrophic Lateral Sclerosis

Parry, Gareth; Rodrigues, Cecília M. P.; Aranha, Márcia M.; Hilbert, Sarah J.; Davey, Cynthia; Kelkar, Praful; Low, Walter C.; Steer, Clifford J.

doi:10.1097/wnf.0b013e3181c47569

Cited by 96 publications

(95 citation statements)

References 23 publications

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“…This versatility is attributed to its multiple mechanisms of action [13]. Besides, clinical [14] and experimental [15] studies verified that the drug crosses the blood-brain barrier. It is now well established that inhibition of hepatocellular apoptosis is one of the main routes for the protective effect of UDCA [16,17].…”

Section: Introductionmentioning

confidence: 92%

Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations

2014

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The recent emergence of ursodeoxycholic acid (UDCA) as a contender in modifying neurotoxicity in human dopaminergic cells as well as its recognized anti-apoptotic and anti-inflammatory potentials in various hepatic pathologies raised impetus in investigating its anti-parkinsonian effect in rat rotenone model. UDCA prominently improved motor performance in the open field test and halted the decline in the striatal dopamine content. Meanwhile, it improved mitochondrial function as verified by elevation of ATP associated with preservation of mitochondrial integrity as portrayed in the electron microscope examination. In addition, through its anti-inflammatory potential, UDCA reduced the rotenone-induced nuclear factor-κB expression and tumor necrosis factor alpha level. Furthermore, UDCA amended alterations in Bax and Bcl-2 and reduced the activities of caspase-8, caspase-9, and caspase-3, indicating that it suppressed rotenone-induced apoptosis via modulating both intrinsic and extrinsic pathways. In conclusion, UDCA can be introduced as a novel approach for the management of Parkinson's disease via anti-apoptotic and anti-inflammatory mechanisms. These effects are probably linked to dopamine synthesis and mitochondrial regulation.

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Section: Introductionmentioning

confidence: 92%

Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations

2014

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“…CSF penetrance of UDCA has been established and the naturally occurring taurine conjugate (TUDCA) is already being tested for its neuroprotective effect in motor neuron disease (Clinical Trials registration: NCT00877604). 25 TUDCA has displayed a partial neuroprotective effect in the Figure 5 Rescue effect of ursodeoxycholic acid in vivo Contrast response functions (CRFs) for the visual response of flies with dopaminergic expression of LRRK2 G2019S compared with those expressing (nonmutant) hLRRK2 or nontransgenic, wild-type controls with matched eye color (WT). CRFs are shown for photoreceptors, lamina neurons, and medulla neurons.…”

Section: G2019smentioning

confidence: 99%

UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2 ^G2019S carriers and in vivo

et al. 2015

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Objective: To further characterize mitochondrial dysfunction in LRRK2 G2019S mutant Parkinson disease (PD) patient tissue (M-LRRK2 G2019S), determine whether ursodeoxycholic acid (UDCA) also exerts a beneficial effect on mitochondrial dysfunction in nonmanifesting LRRK2 G2019S mutation carriers (NM-LRRK2 G2019S), and assess UDCA for its beneficial effect on neuronal dysfunction in vivo.Methods: Intracellular adenosine 59-triphosphate (ATP) levels, oxygen consumption, and activity of the individual complexes of the mitochondrial respiratory chain as well as mitochondrial morphology were measured in M-LRRK2G2019S , NM-LRRK2 G2019S , and controls. UDCA was assessed for its rescue effect on intracellular ATP levels in NM-LRRK2G2019S and in a LRRK2 transgenic fly model with dopaminergic expression of LRRK2 G2019S .Results: Crucial parameters of mitochondrial function were similarly reduced in both M- LRRK2G2019S and NM-LRRK2 G2019S with a specific decrease in respiratory chain complex IV activity. Mitochondrial dysfunction precedes changes in mitochondrial morphology but is normalized after siRNA-mediated knockdown of LRRK2. UDCA improved mitochondrial function in NM-LRRK2 G2019 and rescued the loss of visual function in LRRK2 G2019S flies. Conclusion: There is clear preclinical impairment of mitochondrial function in NM-LRRK2 G2019Sthat is distinct from the mitochondrial impairment observed in parkin-related PD. The beneficial effect of UDCA on mitochondrial function in both NM-LRRK2 G2019S and M-LRRK2 G2019S as well as on the function of dopaminergic neurons expressing LRRK2 G2019S suggests that UDCA is a promising drug for future neuroprotective trials. G2019S 5 manifesting LRRK2 G2019S carriers; NM-LRRK2 G2019S 5 nonmanifesting LRRK2 G2019S carriers; PD 5 Parkinson disease; SSVEP 5 steady-state visual evoked potentials; TUDCA 5 taurine conjugate; UDCA 5 ursodeoxycholic acid.

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“…UDCA is also used to treat extrahepatic ailments [11][12][13][14][15]. It was formerly thought that the choleretic effect of UDCA is what accounted for its mechanism of action [16].…”

Section: Introductionmentioning

confidence: 99%

Testicular immunohistochemical and Ultrastructural changes associated with chronic cholestasis in rats: Effect of ursodeoxycholic acid

Mahmoud

2015

Life Sciences

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Safety, Tolerability, and Cerebrospinal Fluid Penetration of Ursodeoxycholic Acid in Patients With Amyotrophic Lateral Sclerosis

Cited by 96 publications

References 23 publications

Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations

Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations

UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2 ^G2019S carriers and in vivo

Testicular immunohistochemical and Ultrastructural changes associated with chronic cholestasis in rats: Effect of ursodeoxycholic acid

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Safety, Tolerability, and Cerebrospinal Fluid Penetration of Ursodeoxycholic Acid in Patients With Amyotrophic Lateral Sclerosis

Cited by 96 publications

References 23 publications

Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations

Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations

UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2 G2019S carriers and in vivo

Testicular immunohistochemical and Ultrastructural changes associated with chronic cholestasis in rats: Effect of ursodeoxycholic acid

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UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2 ^G2019S carriers and in vivo