Accelerate your path to proof of concept
Explore the most appropriate preclinical strategy for evaluating your therapeutic candidate in CNS disorders.
Generic techniques
Core in vivo and translational methodologies supporting preclinical neuroscience studies across species and indications.
Other Neurosurgical Routes
Description
Other neurosurgical routes are essential for:
- The production of animal models of neurodegenerative diseases by whole central nervous system delivery of viral vectors (e.g. AAV-synuclein or AAV-Abeta) or pathologic peptides (e.g. purified or synthetic synuclein or Abeta).
- The delivery of therapeutic biologics (e.g. growth factors, viral vector, cells) or pharmacological agents into the whole central nervous system.
These can be achieved by acute injection or chronically, after implantation of indwelling catheters.
Method
Several therapeutic agents require intrathecal or intracisternal (cisterna magna) administration to target the spinal cord or the central nervous system.
In rodents, acute direct intrathecal or intracisternal injections are routinely performed by Motac scientists.
In primates, intrathecal (at various levels) or intracisternal administrations are possible after either laminectomy or suboccipital surgical approaches, respectively. Motac staff have unprecedented expertise in these challenging routes of administration.
PK-PD studies (rodents and non-human primates)
Description
Pharmacokinetic (PK) and Pharmacodynamic (PD) experiments in rodents and primates are essential for understanding how a drug behaves in the body (PK) and how the drug affects the body (PD). These studies are critical in preclinical research, helping to assess the efficacy and safety of new therapeutics before they are tested in humans. Motac offers PK/PD services in rodents and macaques to help defining brain penetration and guide dose selection for further pharmacological behavioural studies.
Method
The drug is administered to rodents or macaques via different routes (oral, intravenous, subcutaneous, intrathecal, intracerebral, etc.), and blood and cerebrospinal fluid samples are taken at various time points to measure drug concentration.
Primates provide more accurate data than rodents on drug metabolism and clearance, as they have more human-like enzymes and organ systems. This is particularly important for predicting human pharmacokinetics. The study of drug half-life, bioavailability, and tissue distribution in primates often provides better insights into how the drug will behave in humans.
Endpoints
Motac performs the In Vivo part (administration and sample collection). Bioanalysis is conducted by third parties as pass-through cost. Several vendors are solicited and the customer choses the provider.
PK Parameters:
- Cmax: Maximum plasma concentration of the drug.
- Tmax: Time taken to reach Cmax.
- AUC (Area Under the Curve): Total drug exposure over time.
- Half-Life (T1/2): The time taken for the plasma concentration of the drug to decrease by half.
- Clearance: Rate at which the drug is removed from the body.
PD Parameters:
- Emax: Maximum effect achievable by the drug.
- EC50: Drug concentration at which 50% of the maximum effect is observed.
- Dose-response relationship: Shows how the biological response changes with varying drug doses.
Brain microdialysis (rodents and non-human primates)
Description
Brain microdialysis is a powerful technique used to monitor the chemical environment in specific areas of the brain in real time. It allows to sample the extracellular fluid in the brain to measure neurotransmitters, metabolites, and other molecules (e.g. test items), providing valuable insights into brain function and pathology). Brain microdialysis is widely used in preclinical research to study the dynamics of brain chemistry in various disease states. Microdialysis helps in understanding how brain chemistry changes under pathological conditions, such as during stroke, brain injury, epilepsy, or in neurodegenerative diseases like Parkinson’s and Alzheimer’s. This technique is also particularly suited to study how a test item can affect brain chemistry and in particular the dynamics of release and clearance of brain neurotransmitters over time.
Method
A small, semi-permeable probe is inserted into a targeted brain region using stereotactic surgery to ensure precise placement. A physiological solution, typically artificial cerebrospinal fluid (aCSF), is continuously pumped through the probe. Molecules from the extracellular fluid diffuse across the membrane of the probe and are collected in the outflow for analysis.
It provides continuous sampling, allowing for dynamic measurements over time (up to several hours). The technique can precisely target specific brain regions to measure local changes in chemistry. Although it requires the insertion of a probe, microdialysis is less invasive compared to other techniques and does not typically damage the surrounding tissue.
Motac offers the possibility to conduct microdialysis studies in anesthetised or awake rodents and non-human primates. This is critical in studying brain processes in physiological and pathological states as well as in detecting test item biodistribution or target engagement. Motac is the only CRO enabling such studies in awake and behaving macaques.
References
Thiollier T, Wu C, Porras G, Bezard E, Li Q, Zhang J, Contamin H. Microdialysis in awake macaque monkeys for central nervous system pharmacokinetics. Animal Model Exp Med. 2018 Dec 4;1(4):314-321
Porras G, De Deurwaerdere P, Li Q, Marti M, Morgenstern R, Sohr R, Bezard E, Morari M, Meissner WG. L-dopa-induced dyskinesia: beyond an excessive dopamine tone in the striatum. Sci Rep. 2014 Jan 16;4:3730. doi: 10.1038/srep03730
Vigilance and Sleep in Healthy or Disabled Macaques
Description
The normal sleep pattern may be disrupted in various conditions, such as Parkinson’s disease and Alzheimer’s disease. Drugs also may adversely affect daytime vigilance and attention and disrupt the normal pattern of night- time sleep. This platform permits the simultaneous, chronic, telemetric monitoring of electroencephalogram (EEG), electro-oculogram (EOG) and electromyogram (EMG) in unrestrained, freely moving animals. EOG and EMG signals are required for the detection of rapid eye movement (REM) sleep.
Method
Electrodes are implanted for recording of EEG, EOG and EMG potentials and connected to a subcutaneous telemetry transmitter. The EEG, EOG and EMG signals allow reliable quantification of sleep stages. This is performed semi- automatically using dedicated computer software, with reliability of scoring controlled by a trained sleep clinician with experience in non-human primate sleep analysis.
Endpoints
Data are expressed as hypnograms, depicting the stages of sleep over time.
References
Q. Barraud, V. Lambrecq, C. Forni, S. McGuire, M. Hill, B. Bioulac, E. Balzamo, E. Bezard, F. Tison, I. Ghorayeb, Sleep disorders in Parkinson’s disease: the contribution of the MPTP non-human primate model. Exp Neurol 219, 574- 582 (2009).
C. Hyacinthe, Q. Barraud, F. Tison, E. Bezard, I. Ghorayeb, D1 receptor agonist improves sleep-wake parameters in experimental parkinsonism. Neurobiol Dis 63, 20-24 (2014).
Quantitative Kinematics
Description
In the field of Parkinson’s disease therapeutics research, the behavioural effects of putative new therapies are assessed in primates using “clinical” rating scales that correspond as closely as possible to those used in man. These provide non-parametric data that are vulnerable to observer bias, even when the rater is blinded as to the treatment. There is, therefore, the need for an objective, quantitative and sensitive technique for assessing motor behaviour under various conditions.
Method
We have developed an unbiased methodology that combines video-based, 3-dimensional kinematic analysis with wireless electromyographic recording in non-human primates. Quadrupedal locomotion can be recorded before (OFF) and after treatment (ON).
This can be done:
- Under a range of treadmill velocities or
- In a spontaneous, overground locomotor task that can be made more complicated by the addition of obstacles (e.g. a ladder).
A large number of kinematic parameters are computed in order to measure locomotor control strategies qualitatively and quantitatively.
References
J. Baufreton, T. Milekovic, Q. Li, S. McGuire, E. M. Moraud, G. Porras, S. Sun, W. K. D. Ko, M. Chazalon, S. Morin, E. Normand, G. Farjot, A. Milet, J. Pype, E. Pioli, G. Courtine, B. Bessiere, E. Bezard, Inhaling xenon ameliorates l-dopa- induced dyskinesia in experimental parkinsonism. Mov Disord 33, 1632-1642 (2018).
M. Capogrosso, T. Milekovic, D. Borton, F. Wagner, E. M. Moraud, J. B. Mignardot, N. Buse, J. Gandar, Q. Barraud, D. Xing, E. Rey, S. Duis,
Y. Jianzhong, W. K. Ko, Q. Li, P. Detemple, T. Denison, S. Micera, E. Bezard, J. Bloch, G. Courtine, A brain-spine interface alleviating gait deficits after spinal cord injury in primates. Nature 539, 284-288 (2016).
M. Bourdenx, S. Dovero, M. Engeln, S. Bido, M. F. Bastide, N. Dutheil, I. Vollenweider, L. Baud, C. Piron, V. Grouthier, T. Boraud, G. Porras, Q. Li, V. Baekelandt, D. Scheller, A. Michel, P. O. Fernagut, F. Georges, G. Courtine, E. Bezard, B. Dehay, Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by alpha-synuclein overexpression. Acta Neuropathol Commun 3, 46 (2015).
M. Yin, D. A. Borton, J. Komar, N. Agha, Y. Lu, H. Li, J. Laurens, Y. Lang, Q. Li, C. Bull, L. Larson, D. Rosler, E. Bezard, G. Courtine, A. V. Nurmikko, Wireless Neurosensor for Full-Spectrum Electrophysiology Recordings during Free Behavior. Neuron 84, 1170-1182 (2014).
