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PED has no association with EquiLife or the Laminitis Clinic
On the 4th of October 2004, a 19 month research project commenced examining circadian and circannual peripheral plasma concentrations of biogenic amines in horses diagnosed with Cushing's syndrome and matched controls, under natural photoperiods.
This successfully completed in May 2006 and the outcomes from the project have been presented in a scientific paper, published in the JNE August 2008 edition. The project was supported by the Department of Trade and Industry, the Laminitis Trust and the Horse Trust.
The article is available for download here.
This article was submitted to The Veterinary Review Magazine for publication in the September 2008 issue.
Attitudes to laminitis have changed considerably over the past few decades. Much more research is now available and the condition is generally regarded as a systemic disease (1); setting aside "mechanical laminitis", we tend to think in terms of carbohydrate overload or stressors, with cortisol levels contributing to the clinical signs in many cases (2). Additionally, a variety of different hormone-associated diseases have been proposed to explain why one horse may be particularly susceptible to developing laminitis and another, similar individual, has no apparent problems. For example, "Equine Metabolic Syndrome" (3) or pituitary pars intermedia dysfunction (PPID) (4). However, without a unifying theory for the aetiology or pathophysiology of laminitis, a decision on the most effective treatment still has a component of guesswork.
PED is an early stage, high growth venture founded in 2004 at the BioCity Nottingham Innovation Centre. The company was set up to progress research into the root cause/s of laminitis susceptibility so that treatment could be better targeted for individual equine physiology. A Preferred Partner Scheme for Veterinary Organisations has recently been implemented, where Practices can apply to be part of a network providing PED's new laboratory tests for Cushingoid horses, validated during a recent scientific study (5). The study examined horses highly susceptible to developing laminitis: aged PPID cases (determined by history, external examination and static hormonal determinations) matched to similar controls (judged similar by breed/type, gender, weight and height). Both daily and seasonal rhythms were investigated. It was found that there were statistically significant differences between the groups for individual amines (serotonin and dopamine) and cortisol in the peripheral circulation and also in the ratios of biogenic amines, one to another (6). Of great interest was that dopamine was generally lower in PPID individuals across the seasons but showed rhythm phase shifts (acrophase or peak at a different point in the cycle) and cosinor analysis differences (concentration variance) in June, but particularly in September.
Simon Turner, a Partner at Chine House Veterinary Hospital near Loughborough, Leicestershire, is a co-author of the scientific paper from this study, recently published in the Journal of Neuroendocrinology (August 2008): "The research being carried out by PED could be a very interesting step forward in the fight against laminitis. A simple blood test may be able to help identify "at risk" horses before the disease develops allowing veterinary surgeons to give important management advice and prophylactic treatment." Full "Cushing's" profiles, including industry standard tests (dexamethasone suppression, if required) are available from PED. For example, serotonin:dopamine ratio, ACTH, cortisol, insulin and biochemistries, with the collection protocol being similar to that normally expected for ACTH. Jerry Watkins, Welfare Manager at HorseWorld, Bristol commented, "We could immediately see the welfare potential from pre-emptive testing and were also interested to have new information for horses at our site with pre-existing problems."
PED's new approach builds on previous work, including Dilman et al (6) in human medicine and Bailey at al (7) in veterinary research: that independently occurring laminitis is a manifestation of a transient, acute biogenic amine imbalance, whereas laminitis within a disease (such as Cushing's syndrome) is a cumulative, chronic imbalance of the same type. Biogenic amines include serotonin and dopamine and are any of a group of naturally occurring, biologically active amines which act primarily as neurotransmitters and are capable of affecting mental functioning and of regulating blood pressure, body temperature, and other bodily processes. PED researchers believe that the often observed high glucose, insulin and cortisol concentrations in the peripheral circulation of a laminitic, or individual susceptible to laminitis, are as a result of an imbalance higher in the neurohormonal cascade of control, i.e. an imbalance associated with the pineal, hypothalamus and pituitary glands.
At present, it appears that the majority of work in this area has been carried out in regard to the central nervous system, with valuable contributions such as those by McFarlane et al (8) describing the degradation of hypophyseal dopaminergic neurones in PPID. Dopamine is a neurotransmitter produced from the amino acid tyrosine by the neurons in substantia nigra and striatum and released as a neurohormone by the periventricular hypophysis in the hypothalamus; it is also found in the amacrine cell of the retina of some species. Serotonin is synthesized from the amino acid tryptophan and is found mainly in the pineal gland. It has been discovered that both dopamine and serotonin decline, as the age increases, in human and other mammals (6). Additionally, if a graph of the decline is plotted against years, the rate of decrease of dopamine is much greater than that of serotonin. This does not appear to have been scientifically studied in the horse, despite cyproheptadine and pergolide being drugs of choice in the treatment of PPID! Also, it is perhaps not surprising to observe decline in both of these neurotransmitters in the aged individual considering that the enzymatic activity of monoamine oxidase (MAO) in the brain increases with age and the main substrates for this enzyme are believed to be dopamine and serotonin. With oxidative stress described as one of the causes in HPA axis up-regulation in the medical literature and loss of dopaminergic inhibition of POMC-derived peptide secretion generally accepted as a cause of PPID, an investigation of these neurohormones (or biogenic amines) in the equine peripheral circulation seems timely.
Figure 1: Pony diagnosed with PPID. Note the lack of neck muscle and "curly" coat despite the summer months being well underway.
Figure 2: The same pony, lateral view (summer coat).
Clinical signs of Cushing's disease, including recurrent laminitis.
Figure 3: The same pony after "rebalancing"
treatment (winter coat).
Figure 4: The same pony: close up of improvement in coat following "rebalancing" treatment.