22/05/2018

Migraine: The culprits behind the headache?

Migraine is not just a simple headache. Very often it is accompanied by various symptoms such as nausea, sensitivity to light, noise and visual disturbances, it is characterised by a unilateral throbbing pain sensation that can last for up to 72 hours and is accentuated during physical exercise. 1 in 7 people suffers from migraine and although it is not correlated with age or social background, women tend to suffer twice as much than men. In the UK alone, it is estimated that migraine costs £2 billion a year, hence extensive research is being carried out to develop effective treatments.[1]

Headaches in Migraine – The Crucial Role of CGRP
The headache phase in the migraine occurs when the dilated blood vessels mechanically activate the perivascular trigeminal sensory nerve fibres, the principle sensory nerve in the head. This triggers a pain response with several neurotransmitters, such as substance P and CGRP (calcitonin gene–related peptide), being released to transmit the nociceptive signals from the trigeminal sensory afferents to second-order neurons. CGRP, a potent vasodilator, will aggravate the dilation of cranial blood vessels, cause mast-cell degranulation and initiate neurogenic inflammation within the meninges. As a result, prolonged activation of the meningeal trigeminal nerves, vessels and mast cells causes sensitisation of secondary and tertiary-order neurons which could explain symptoms associated with migraine such as allodynia (skin sensitivity) and photosensitivity.[2]

The role played by CGRP in migraine headaches is widely accepted. Indeed, it has been observed that during a migraine attack, the levels of CGRP in blood and saliva were increased.[3] It was also shown that administrating CGRP to patients prone to migraines resulted in inducing migraine-like headaches.[4]

The Controversial Role of TRPV1 in Migraine Pathology
More recently, it has been shown that the cation channel TRPV1, a nonselective cation channel that is activated by stimuli such as high temperature and capsaicin could also be involved in migraine pathophysiology. Colocalised with CGPR in trigeminal ganglion neurons, TRPV1 when activated promotes the release of CGPR.

It is also known that patients suffering from chronic migraine show elevated levels of nerve growth factor (NGF) in the cerebral spinal fluid and it has been suggested that a NGF-dependent mechanism could lead to the insertion of TRPV1 into the plasma membrane hence increasing the number of TRPV1 channels available for activation on the nociceptor surface membrane. In addition, several studies have also demonstrated that through different pathways, prostaglandins, ATP, BK and possibly NGF reduce the TRPV1 activation threshold by phosphorylating TRPV1 on S502 and S800 and hence causing sensitisation.[5]

Based on this, TRPV1 antagonists seemed to be attractive targets for the treatment of migraine and SB-705498, a TRPV1 antagonist showed promising results in cats. However, in the case of humans, the clinical trial was terminated early due to a lack of efficacy in treating acute migraine.[6] More recently, two TRPV1 receptor antagonists have been shown to be effective in two different experimental models of migraine suggesting that further clinical trials using different TRPV1 antagonists should be performed to better understand the role played by TRPV1 in migraine pathology.[6]

Working with TRPV1? Have a look at our products:

Biosensis Antibodies to TRPV1 Cat. No.
Rabbit antibody to human capsaicin receptor (531-541): whole serum R-053-100
Rabbit antibody to human capsaicin receptor (608-621): whole serum R-076-100
Mouse monoclonal antibody to rat capsaicin receptor (VR1, TRPV1, 819-838), [Clone BS397]: IgG M-1714-100
StressMarq Small Molecules Cat. No.
Capsaicin (TRPV1 opener) SIH-322
BCTC (TRPV1 blocker) SIH-307
SB-366791 (TRPV1 blocker) SIH-321

Current and Emerging Treatments


Current migraine treatments include the use of nonsteroidal anti-inflammatory drugs (NSAID) such as aspirin, ibuprofen, naproxen and didofenac potassium. When the pain is moderate to severe, triptans (highly selective serotonin 5-HT1B and 5-HT1D receptor agonists) are considered to be the first line of treatment. Indeed, serotonin vasoconstricts the nerve endings and blood vessels and consequently affects nociceptive pain. [7]

However, because of the presence of the 5-HT1B receptors on blood vessels and the vascular risks associated with the use of these drugs, ditans, a novel class of chemicals selectively targeting the 5-HT1F receptors expressed in the trigeminal nerve pathway but lacking the vasoconstrictive properties, are being developed. Currently, lasmiditan is in phase III clinical trials in the US. [8]

As seen previously, CGRP plays an important role in the pathogenesis of migraine and as a result, several small molecules, CGRP receptor antagonists called gepants have been developed. In particular, telcagepant and MK-3207 were shown to be effective treatments for acute migraine, but were terminated due to their liver toxicity.[2] Other drugs based on monoclonal antibodies are currently being developed. These new treatments target either CGRP or the CGRP receptors and currently show promising results in human clinical trials. Aimovig (erenumab) developeed by Amgen and Novartis has recently been FDA-approved as a preventive migraine treatment by blocking the activity of CGRP receptors.[9]

Migraine Research: ImmunoStar Antibodies can help
ImmunoStar has developed an excellent range of antibodies for neuroscience research. These antibodies are put through extensive testing before release to ensure they are both high quality and high titer. This provides excellent reliability and lot-to-lot consistency. They have also been specifically tested for use in immunohistochemistry. They are currently available to purchase through Newmarket Scientific.

Migraine related articles using antibodies from the ImmunoStar range can be found below:

References ImmunoStar antibodies
Neural mechanism for hypothalamic-mediated autonomic responses to light during migraine,
Noseda R et al, PNAS, 2017, 114 (28): E5683-E5692
Tyrosine hydroxylase, oxytocin, vasopressin 1
Hypothalamic and basal ganglia projections to the posterior thalamus: Possible role in modulation of migraine headache and photophobia;
Kagan R et al, Neuroscience 2013, 248, 359-368
Tyrosine hydroxylase, cholecystokinin octapeptide (CCK8)
Neurochemical Pathways That Converge on Thalamic Trigeminovascular Neurons: Potential Substrate for Modulation of Migraine by Sleep, Food Intake, Stress and Anxiety,
Noesda R et al, Plos one 2014, 9 (8): e103929
Tyrosine hydroxylase
Dopamine β-Hydroxylase Statins Decrease Expression of the Proinflammatory Neuropeptides Calcitonin Gene-Related Peptide and Substance P in Sensory Neurons,
Bucelli RC et al, J. Pharmacol Exp Ther, 2008, 324 (3): 1172-1180 
Substance P

References:
[2] Migraine, Dodick DW, The Lancet, 2018, 391 (10127), 1315-1330
[3] Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Goadsby PJ et al, Ann Neurol. 1990;28:183–7.
[4] Elevated saliva calcitonin gene-related peptide levels during acute migraine predict therapeutic response to rizatriptan. Cady RK et al. Headache. 2009;49:1258–66.
[5] TRPV1 in migraine pathophysiology, Meents JE et al, Trends in Molecular Medicine, 2010, 16 (4):153-159
[6] Two TRPV1 receptor antagonists are effective in two different experimental models of migraine, Meents JE et al, The Journal of Headache and Pain, 2015, 16:57
[7] CGRP and serotonin in migraine, Aggarwal M et al, Annal od Neurosciences, 2012 19 (2): 88-94 https://www.researchgate.net/publication/265558756_Serotonin_and_CGRP_in_migraine
[8] Migraine Therapy: Current Approaches and New Horizons,  Goadsby PJ et al, Neurotherapeutics, 2018, 15 (2) :271-273
[9] https://www.genengnews.com/gen-news-highlights/amgen-novartis-set-to-launch-migraine-drug-aimovig-next-week-after-fda-approval/81255834 Accessed on 21/05/2018


Written by Magalie Dale
If you like my post why not connect to me on LinkedIn.

09/05/2018

Amyloid beta plaque staining

Alzheimer's disease is characterised by a gradual decline of the cognitive functions and it is accepted that one of its hallmarks is the accumulation of insoluble proteinaceous deposits called amyloid fibrils. Originally thought to be carbohydrate in nature as they could be stained in tissues with iodine, they were called amyloids as iodine was a well-known stain for polysaccharides such as amylose. It was later discovered they were actually constituted of proteins fibres (mostly amyloid beta 1-40 and amyloid beta 1-42), but for historic reasons, the name was conserved.
Histologic dyes such as Congo Red or Thioflavin S or T show affinity for the amyloid plaques. Although they are commonly used for amyloid plaques detection, they come with several limitations, firstly in their spectral properties, with both having a broad range of excitation frequencies leading to a "bleed through" when illuminated with other filters and secondly by requiring harsh chemicals making it less compatible with subsequent use of antibodies.
Amylo-Glo RTD (Cat. No. TR-300-AG) is a new histological marker developed by Biosensis (Thebarton, South Australia) that shows clear superiority for visualising amyloid plaques over these conventional markers (Schmued et al., 2012).
  1. Amylo-Glo shows the same affinity as conventional probes (Congo red, ThioflavinS and Pan abeta 40) and is suitable to use with fresh, frozen, and formalin-fixed immunohistochemistry or cytochemistry.
  2.  Amylo-Glo has a unique emission/excitation profile. Only excitable with UV light and emits a bright blue/yellow colour.
  3.  Amylo-Glo only uses mild conditions making it ideal for subsequent immunohistochemistry labelling.
  4.  Its chemical and spectral properties allow for multi-labelling studies. Its specific blue fluorescence contrasts effectively with red and green immunofluorescence labelling.
  5. Amylo-Glo is perfect for low magnification studies. Indeed, its unusual brightness (5-6 times brighter than conventional probes) allows to generate strong signals at extremely low magnification (x2).

This triple exposure allows for the simultaneous localization of Amylo-Glo® positive amyloid plaques (blue), GFAP positive hypertrophied astrocytes (green) and activated microglia (red) in the hippocampus of the AD/Tg mouse. Combined UV, blue and green light illumination.




Amylo-Glo UV illumination only






Datasheet available on www.newmarketscientific.com.

Biosensis Amylo-Glo RTD is also available with an ethidium bromide counter stain (Cat. No TR-400 AG) for a quick and effective way to visualise amyloid plaques as well cell nuclei and cell bodies of cells while under UV illumination in one step.
Both products are currently available to purchase in the UK and Ireland through Newmarket Scientific, the new distributor of Biosensis.

Reference:
Schmued L. et al, Journal of Neuroscience Methods 209 (2012), 120-126

To learn more about Alois Alzheimer:
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01/05/2018

Environmental stress in Plants

Extreme temperatures, high/low light intensity, draught, flooding, salinity are, to name a few, stressors that plants will be repeatedly subjected to over the course of their life-time. As a result, due to their "sedentary life-style", plants must adapt quickly to their ever-changing environment if they want to survive. Understanding how plants sense, respond and adapt to these stressors is of primordial importance since it has recently been estimated that the temperature increase due to global warming this century will likely exceed previous predictions,[1] hence increasing environmental stress on plants not only by their intensity but also by their frequency. As plant domestication occurred under more favourable conditions than during the early evolution of land plants, crops have been selected on their productivity rather than on their resistance to abiotic stress and with the world population predicted to reach 9.7 billion by 2050, plant scientists face one of the biggest challenge of the future: increasing crop production on less area and with dwindling resources of water.[2]

How do plants respond to draught stress?
It is usually assumed that plant response to stress happens in three different phases.[3]
  1. An alarm phase, when plants detect a change in their environment and activate different mechanisms to be able to cope with the change.
  2. A resistance phase, where plants adjust their structure and function in order to withstand the stress and repair the damaged caused.
  3. If the stressor stops or lessens then the plant may recover and reach a new optimal physiological status. However, if the stress continues or is too intense, then the plant dies.
In the specific case of draught stress, plants are known to reduce photosynthesis by decreasing their leaf area as well as their photosynthesis rate, mainly by inhibiting the CO2 mechanism and by restricting the diffusion of CO2 into the leaf via stomatal closure. As a result of this and because of the low concentration of intracellular CO2, ongoing photosynthetic light reactions may cause the building-up of reduced photosynthetic electron transport components, which can react with molecular oxygen to form highly damaging reactive oxygen species (ROS).[4]

As a result, plants cope with stress by modulating key physiological processes that result in the modification of molecular and cellular processes. This plasticity is mediated by phytohormones such as abscisic acid (ABA), ethylene, cytokinin (CK), gibberellic acid (GA) and auxin as they play important roles in every step of plant development and hence will enable a plant to respond to abiotic stress. For instance, under drought stress, ABA is involved in stomatal closure whereas cytokinins are known to delay leaf senescence and death.[4]

Agrisera antibodies - Working towards a better understanding of environmental stresses in plant research

Development of crops and plants highly resilient to environmental stresses without compromising on yield is one of the many challenges that plant scientists are currently facing. To facilitate research in this area, Agrisera has developed an extensive range of plant antibodies. This includes environmental stress antibodies as well as phytohormone antibodies.



References:
1. Greater future global warming inferred from Earth’s recent energy budget, Brown PT et al, Nature 2017, 552, 45–50
2. Plant abiotic stress challenges from the changing environment; Pereira A, Front Plant Sci., 2016; 7: 1123.
3. Stress Memory and the Inevitable Effects of Drought: a physiological perspective; Fleta-Soriano E et al, Front Plant Sci, 2016,7, 143
4. Plant adaptation to drought stress, Basu S et al, Version 1. F100Res. 2016; 5: 1554.


Written by Magalie Dale
If you like my post why not connect to me on LinkedIn.