Related Experiment Video

Updated: Jun 29, 2025

A Method to Study α-Synuclein Toxicity and Aggregation Using a Humanized Yeast Model
08:24

A Method to Study α-Synuclein Toxicity and Aggregation Using a Humanized Yeast Model

Published on: November 25, 2022

2.2K

C9-Functionalized Doxycycline Analogs as Drug Candidates to Prevent Pathological α-Synuclein Aggregation and

Clémence Rose1, Rodrigo Hernán Tomas-Grau2, Brenda Zabala3

  • 1BioCIS, CNRS, Université Paris-Saclay, 91400, Orsay, France.

Chemmedchem
|March 25, 2024
PubMed

Insights

Novel doxycycline derivatives were developed to treat Parkinson's disease (PD) without antibiotic effects. Two compounds effectively inhibited alpha-synuclein aggregation and reduced neuroinflammation, showing promise for PD therapy.

Area of Science:

  • Medicinal Chemistry
  • Neuroscience
  • Pharmacology

Background:

  • Doxycycline, a tetracycline antibiotic, exhibits anti-inflammatory and antioxidant properties beneficial for Parkinson's disease (PD).
  • Its antibiotic activity limits long-term use in PD patients, necessitating the development of non-antibiotic alternatives.
  • Doxycycline's ability to inhibit alpha-synuclein aggregation is a key mechanism for potential PD treatment.

Purpose of the Study:

  • To design and synthesize novel doxycycline derivatives with reduced antimicrobial activity but retained therapeutic properties for PD.
  • To evaluate the efficacy of these derivatives in inhibiting alpha-synuclein aggregation and reducing neuroinflammation.
  • To identify promising drug candidates for Parkinson's disease treatment through structure-activity relationship studies.

Main Methods:

  • Eighteen novel doxycycline derivatives were synthesized, modifying the C4 and C9 positions.
  • The Thioflavin-T assay was used to assess the inhibition of alpha-synuclein aggregation.
  • In vitro studies using microglial cell cultures modeled Parkinson's disease neuroinflammatory processes to evaluate anti-inflammatory effects.

Main Results:

  • Seven synthesized compounds demonstrated superior inhibition of alpha-synuclein aggregation compared to doxycycline.
  • Two derivatives exhibited enhanced anti-inflammatory effects in microglial cell models of PD.
  • Structure-activity relationship studies guided the identification of lead compounds.

Conclusions:

  • Two novel doxycycline derivatives show significant potential as non-antibiotic therapeutic agents for Parkinson's disease.
  • These compounds effectively target key PD pathomechanisms, including alpha-synuclein aggregation and neuroinflammation.
  • Further development of these tetracycline derivatives could lead to new treatments for Parkinson's disease.
Keywords:
Parkinson diseaseaggregationalpha-synucleinanti-inflammationtetracycline

More Related Videos

Analyzing the Parkinson's Disease Mouse Model Induced by Adeno-associated Viral Vectors Encoding Human α-Synuclein14:45

Analyzing the Parkinson's Disease Mouse Model Induced by Adeno-associated Viral Vectors Encoding Human α-Synuclein

Published on: July 29, 2022

5.9K
Technique for Intranasal Administration of α-Synuclein Aggregates04:49

Technique for Intranasal Administration of α-Synuclein Aggregates

Published on: November 8, 2024

452

Related Concept Videos

Parkinson's Disease: Treatment01:24

Parkinson's Disease: Treatment

Neurodegenerative disorders, such as Parkinson's Disease (PD), involve the gradual and irreversible destruction of neurons in particular brain areas. These disorders exhibit standard features like proteinopathies, selective vulnerability of some neurons, and an interaction of intrinsic properties, genetics, and environmental influences in neural injury.
Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of...
264
Parkinson's Disease: Overview01:15

Parkinson's Disease: Overview

Neurodegenerative disorders are progressive diseases that cause irreversible damage and loss to neurons in specific brain areas. Examples of these disorders include Parkinson's disease, Alzheimer's disease, Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS). These disorders share characteristics such as proteinopathies, selective neuronal vulnerability, and a complex interplay between genetic and environmental factors. The primary therapeutic goal for these conditions is...
541
Drugs Affecting Neurotransmitter Synthesis01:29

Drugs Affecting Neurotransmitter Synthesis

Drugs affecting neurotransmitter synthesis can impact the adrenergic neuron and the synthesis of neurotransmitters. For example, α-methyltyrosine and carbidopa target specific enzymes involved in catecholamine synthesis. α-methyltyrosine inhibits the enzyme tyrosine hydroxylase, which converts tyrosine into dopamine. By blocking this enzyme, α-methyltyrosine reduces dopamine production and other catecholamines. Carbidopa, on the other hand, inhibits the enzyme dopa decarboxylase,...
1.4K
Alzheimer's Disease: Treatment01:22

Alzheimer's Disease: Treatment

Alzheimer's Disease (AD), a neurodegenerative disorder, is pathologically identified by amyloid plaques and neurofibrillary tangles composed of tau protein. AD pharmacotherapy aims to manage cognitive symptoms, delay disease progression, and treat behavioral symptoms. The treatment is primarily symptomatic and palliative, with no definitive disease-modifying therapy available. Cholinesterase inhibitors, including donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne), are...
184
Drugs Affecting Neurotransmitter Release or Uptake01:21

Drugs Affecting Neurotransmitter Release or Uptake

Certain drugs can affect how neurotransmitters called catecholamines, are released or taken back up in the adrenergic neuron. They can have different effects on the body's sympathetic transmission. Reserpine, a natural compound found in the Rauwolfia shrub, blocks a transporter called vesicular monoamine transporter (VMAT), which leads to a buildup of catecholamines in the cell and reduces sympathetic transmission. Another drug called guanethidine works in multiple ways, including blocking...
1.0K
Lysosomal Hydrolases01:22

Lysosomal Hydrolases

Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
3.8K