Safe drugs to fight mutant protein overload and alpha-1-antitrypsin deficiency

Sechi, GianPietro; Balbi, Pietro; Bachetti, Tiziana; Ceccherini, Isabella

doi:10.1016/j.jhep.2011.03.033

Cited by 4 publications

(4 citation statements)

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“…Instead, prolonged, longitudinal single patient studies may be a useful approach to identify new therapeutic strategies in this disorder (Sechi et al 2010a). The successful clinical outcome related to ceftriaxone documented in our patient highlights the possibility that this safe drug may be useful for other AxD patients and puts the relevant question whether ceftriaxone may also be useful in treating other diseases caused by intracellular accumulation and aggregation of misfolded proteins (Sechi et al 2011), particularly other neurodegenerative diseases with astrocyte involvement.…”

Section: Discussionmentioning

confidence: 75%

Ceftriaxone for Alexander’s Disease: A Four-Year Follow-Up

et al. 2012

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In 2010, we reported the successful clinical outcome related to a 20-month course of intravenous, cyclical ceftriaxone, in a patient with adult-onset Alexander's disease. We now provide evidence that the progression of the patient's signs/symptoms was halted and reversed with a 4-year-long extension of the trial.The patient's clinical signs/symptoms were evaluated before the start and every 6 months for 6 years. For the early 2 years, without therapy, and for the following 4 years, after intravenous ceftriaxone 2 g daily, for 3 weeks monthly during the initial 4 months, then for 15 days monthly.Gait ataxia and dysarthria were assessed clinically on a 0 to 4 scale. Palatal myoclonus and nystagmus/oscillopsia were monitored by videotape and a self-evaluation scale. The degree of disability, measured by a modified Rankin scale, and the brain MRI were periodically evaluated.Before ceftriaxone therapy, in a 2-year period, gait ataxia and dysarthria worsened from mild to marked, palatal myoclonus spread from the soft palate to lower facial muscles, and the patient complained of oscillopsia. After 4 years of ceftriaxone therapy, gait ataxia and dysarthria improved, from marked to mild at clinical rating scales. The palatal myoclonus was undetectable; the patient did not complained of oscillopsia and declared a progressively better quality of life. Ceftriaxone was safe.This case report provides Class IVevidence that intravenous cycles of ceftriaxone may halt and/or reverse the progression of neurodegeneration in patients with adult-onset Alexander's disease and may significantly improve their quality of life.

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Section: Discussionmentioning

confidence: 75%

Ceftriaxone for Alexander’s Disease: A Four-Year Follow-Up

et al. 2012

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“…CBZ, in particular, which has a very safe profile, has been revealed to be the most effective treatment in rescuing the correct pattern of mutant GFAP in the model. These findings may have important implications for better understanding the pharmacology of AxD and other neurodegenerative disorders caused by different misfolded proteins ( Sechi et al, 2011 ; Ruzza et al, 2014 ) in particular for qualitative/quantitative structure-activity relationship studies. Moreover, our observations have a considerable clinical relevance because of the safer profile of CBZ compared to CLM and PHT in clinical practice.…”

Section: Discussionmentioning

confidence: 91%

Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease

et al. 2021

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Alexander’s disease (AxD) is a rare, usually relentlessly progressive disorder of astroglial cells in the central nervous system related to mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP). The pathophysiology of AxD is only partially understood. Available data indicate that an excessive GFAP gene expression may play a role. In particular, a “threshold hypothesis” has been reported, suggesting that mutant GFAP representing about 20% of the total cellular GFAP should be sufficient to cause disease. Thus, strategies based on reducing cellular mutant GFAP protein levels and/or activating biological processes involved in the correct protein folding could be effective in counteracting the toxic effect of misfolded GFAP. Considering that clomipramine (CLM), which has been selected by a wide small molecules screening as the greatest inhibitory potential drug against GFAP expression, is contraindicated because of its proconvulsant activity in the infantile form of AxD, which is also characterized by the occurrence of epileptic seizures, two powerful antiepileptic agents, carbamazepine (CBZ) and phenytoin (PHT), which share specific stereochemical features in common with CLM, were taken into consideration in a reliable in vitro model of AxD. In the present work, we document for the first time that CBZ and PHT have a definite inhibitory effect on pathological GFAP cellular expression and folding. Moreover, we confirm previous results of a similar beneficial effect of CLM. In addition, we have demonstrated that CBZ and CLM play a refolding effect on mutant GFAP proteins, likely ascribed at the induction of CRYAB expression, resulting in the decrease of mutant GFAP aggregates formation. As CBZ and PHT are currently approved for use in humans, their documented effects on pathological GFAP cellular expression and folding may indicate a potential therapeutic role as disease-modifying agents of these drugs in the clinical management of AxD, particularly in AxD patients with focal epilepsy with and without secondary generalization.

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“…In our opinion, in virtue of their accessibility, well-known and safe drugs such as ceftriaxone, potentially able to bind to proteins involved in the formation of amyloid-like aggregates, and to inhibit their production, are of immense interest as potential leads for therapeutic intervention in PD and other degenerative disorders caused by intracellular accumulation and aggregation of misfolded proteins. 8 Since, at the molecular level, neuronal α-synuclein inclusions and pathological α-synuclein transmission play a leading role in initiation and progression of Parkinson-like neurodegeneration, 9,10 and on account of the capability of ceftriaxone to reduce the intracytoplasmic aggregates of mutant GFAP, 3 we thought of investigating, by circular dichroism (CD) spectroscopy, the capability of ceftriaxone to interact with α-synuclein. Moreover, we studied the protective effect of ceftriaxone on PC12 cells exposed to the neurotoxic compound 6-hydroxydopamine (6-OHDA).…”

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confidence: 99%

“…Notably, although ceftriaxone seems to have a definite role in counteracting neurodegeneration in several neurodegenerative disorders, its molecular interaction with α-synuclein has not been reported. In our opinion, in virtue of their accessibility, well-known and safe drugs such as ceftriaxone, potentially able to bind to proteins involved in the formation of amyloid-like aggregates, and to inhibit their production, are of immense interest as potential leads for therapeutic intervention in PD and other degenerative disorders caused by intracellular accumulation and aggregation of misfolded proteins …”

mentioning

confidence: 99%

Ceftriaxone Blocks the Polymerization of α-Synuclein and Exerts Neuroprotective Effects in Vitro

Ruzza¹,

Siligardi

Hussain

et al. 2013

ACS Chem. Neurosci.

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ABSTRACT:The β-lactam antibiotic ceftriaxone was suggested as a therapeutic agent in several neurodegenerative disorders, either for its ability to counteract glutamate-mediated toxicity, as in cerebral ischemia, or for its ability to enhance the degradation of misfolded proteins, as in Alexander's disease. Recently, the efficacy of ceftriaxone in neuroprotection of dopaminergic neurons in a rat model of Parkinson's disease was documented. However, which characteristics of ceftriaxone mediate its therapeutic effects remains unclear. Since, at the molecular level, neuronal α-synuclein inclusions and pathological α-synuclein transmission play a leading role in initiation of Parkinson-like neurodegeneration, we thought of investigating, by circular dichroism spectroscopy, the capability of ceftriaxone to interact with α-synuclein. We found that ceftriaxone binds with good affinity to α-synuclein and blocks its in vitro polymerization. Considering this finding, we also documented that ceftriaxone exerts neuroprotective action in an in vitro model of Parkinson's disease. Our data, in addition to the findings on neuroprotective activity of ceftriaxone on Parkinson-like neurodegeneration in vivo, indicates ceftriaxone as a potential agent in treatment of Parkinson's disease.

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Safe drugs to fight mutant protein overload and alpha-1-antitrypsin deficiency

Cited by 4 publications

References 8 publications

Ceftriaxone for Alexander’s Disease: A Four-Year Follow-Up

Ceftriaxone for Alexander’s Disease: A Four-Year Follow-Up

Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease

Ceftriaxone Blocks the Polymerization of α-Synuclein and Exerts Neuroprotective Effects in Vitro

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