- Parkinsonís disease is a neurodegenerative disorder that affects movement.
- Doxycycline antibiotic could offer new hope in the treatment of Parkinsonís disease.
- The drug could be prescribed at low doses for treating Parkinsonís disease.
Doxycycline antibiotic has been used for over half a century to treat bacterial infections. The drug can be prescribed at low doses to be used for the treatment of Parkinson's disease, suggests a new study published in the journal Scientific Reports.
The drug substance was found to reduce the toxicity of α-synuclein, which is a protein, that under certain conditions could form abnormal accumulations of aggregates in the central nervous system cells.
The death of the dopaminergic neurons is the event that is related to the development of symptoms like tremor, slow voluntary movements, stiffness among others.
The study supported by FAPESP included three Brazilian scientists Elaine Del-Bel, Leandro R.S. Barbosa, Rosangela Itri.
Del-Bel told, "We have exciting data from experiments with mice and great expectations that the neuroprotective effect will also be observed in human patients."
"This treatment could stop Parkinson's from progressing, and we therefore plan to start a clinical trial shortly."
The research discovery, fortunately, happened five years ago when Marcio Lazzarini, former student of Del-Bei pursued post doctoral studies at the Max Planck Institute of Experimental Medicine in Germany.
Scientists have found possible alternative treatments for Parkinson's mice experiments; the group has to be used for a well-known model for inducing conditions which are similar to the human disease.
A neurotoxin 6-hydroxydopamine (6-OHDA) is administered to cause the death of the dopaminergic neurons.
Del-Bel said, "To our surprise, only two of the 40 mice given 6-OHDA developed symptoms of Parkinsonism, while the rest remained healthy."
"A lab technician realized the mice had mistakenly been fed chow containing doxycycline, so we decided to investigate the hypothesis that it might have protected the neurons."
The research group has repeated the experiment, a second group of animals has been given doxycycline in low doses by peritoneal injection. Both cases were found to be successful.
Neuroprotective Effect of Doxycycline
Recent research study was conducted to find the mechanisms behind the neuroprotective effects of doxycycline.
In the new trials that involved structural and spectroscopic characterization methods, the protein α-synuclein is considered to be one of the leading cause of dopaminergic neuron death.
Itri said, "α-Synuclein is a small unstructured protein that, in the presence of the cellular membrane, aggregates to form fibrils with multiple regularly ordered layers of beta- sheets along the axis. We call these amyloid fibrils. It's been proven that large amyloid fibrils of this protein aren't toxic to cells; what damages cells is the so-called oligomeric stage formed by small amounts of aggregated α-synuclein. These oligomers can damage neuron membranes."
The research team also synthesized small oligomers of α-Synuclein protein that was conducted in vitro trials to find out if the drug interfered in the process of aggregation and fibril formation.
A combination of three distinct techniques namely nuclear magnetic resonance, x-ray scattering and infrared spectroscopy found to observe two different situations:
- Medium without doxycycline - α-Synuclein were aggregated and may begin forming amyloid fibrils
- Medium with doxycycline - α-Synuclein formed another type of aggregate with different shape and size
The tests were performed in the immortalized human neuroblastoma cells. By using transmission electron microscopy, the group has observed that the presence of the doxycycline in the culture medium has reduced α-Synuclein aggregation by more than 80%
Del-Bel said, "As a result, cell viability increased by more than 80%"
The effects of doxycycline treatment on mice have also been investigated.
"We haven't published any data yet, but I can say right away that doxycycline improves the symptoms of the disease in the animal model."
"Preliminary results suggest that besides its anti-inflammatory action via a reduction in the release of some cytokines, doxycycline also alters the expression of key genes for the development of Parkinson's," added Del-Bel.
According to Del-Bel, the evidence in the scientific literature also shows that α-Synuclein may form aggregates on and causes damage to not just neurons but also astrocytes and other glial cells.
Apart from Parkinson's disease, the process is often associated with the development of other neurodegenerative diseases, like Lewy body dementia (LBD) which is the second most common neurodegenerative disease after Alzheimer's. Further research will help to investigate whether doxycycline could have a beneficial effect.
- Florencia GonzŠlez-LizŠrraga, Sergio B. SocŪas, Cťsar L. Ńvila, Clarisa M. Torres-Bugeau, Leandro R. S. Barbosa, Andres Binolfi, Julia E. Sepķlveda-DŪaz, Elaine Del-Bel, Claudio O. Fernandez, Dulce Papy-Garcia, Rosangela Itri, Rita Raisman-Vozari, Rosana N. ChehŪn. Repurposing doxycycline for synucleinopathies: remodelling of α-synuclein oligomers towards non-toxic parallel beta-sheet structured species. Scientific Reports, 2017; 7: 41755 DOI: 10.1038/srep41755