In horses affected by chronic OA, the main goal of a symptomatic therapy, is the reduction of the pain aimed to improve the quality of life of the patient; moreover, although symptomatic therapies rarely contribute to an optimal recovery of the functionality of the limbs, they are essential to prevent the degeneration of the clinical condition of the horse [23
]. These therapeutic protocols are generally based on NSAIDs that are not suitable for long-term treatments, because they cause undesirable side effects (e.g., gastritis). Therefore, in recent years, alternative therapeutic approaches to NSAIDs, that might improve the patient’s clinical condition over time, or at least stabilize it [24
], are more frequently taken into consideration. CSE, whose anti-inflammatory properties have been preliminarily tested in laboratory animals, is prescribed, in the form of dietary supplement, for the treatment of chronic arthritis and osteoporotic diseases in humans. The active compounds contained in CSE that are thought to behave as competitive inhibitors for COX (cyclooxygenase) and LOX (lipoxygenase) [26
], are supposed to produce analgesic and anti-inflammatory activities by inhibiting, through the same molecular mechanisms of NSAIDs (for this reason CSE is also called crypto-NSAID), the synthesis of leukotrienes and prostaglandins [26
]. With regard to the effects of CSE on the symptoms of horses affected by chronic OA, the present study has shown that, only at the highest dosage tested of 30 g BID, do the score values of both sensitivity and amplitude of passive limb flexion, and the score values of the global flexion test, exhibit progressive, positive variations during the 59 days of product administration. In particular, the sensitivity to passive flexion decreased for all the horses from T0 to T59, and in the case of the subjects with the highest initial score values (Nos 18 and 19), it started to increase after the suspension of the CSE treatment (Figure 2
B). Sensitivity to passive flexion, whose evaluation is determined in response to the mobilization of the main joints (carpus/tarsus, interphalangeal) of the limb imposed by the veterinarian, is an indicator of the degree of pain, due to osteoarticular damage; therefore, even in the absence of a statistical significance (Figure 2
E), since the sensitivity of the passive flexion improves during the administration of the product in the two horses with the highest initial scores, it is plausible to suppose that CSE performs an analgesic action by reducing the pain response to limb flexion. The time profiles of the scores of the amplitude to passive flexion (Figure 2
A), although not statistically significant (Figure 2
D), reveal an improvement of the values in the two subjects exhibiting the most evident symptomatology at T0. This evidence could support the analgesic efficacy of CSE that had been hypothesized from the data of the sensitivity of the passive flexion. As further support to this hypothesis, the statistical relevance of the improvement in the clinical symptomatology obtained from the evaluation of the score values of the global flexion tests (Figure 2
C,F) must be considered. This parameter, in general, evaluates the severity of the lameness (even in the asymptomatic form) as a function of time. In particular, if a joint affected by a chronic pathology (regardless of the etiology) is subjected to a flexion test, during the movement phase, there is a worsening of the limping of the subject, which is more severe as the symptom correlated to pain, lasts longer. In particular, the statistical analysis shows a significant improvement for all the CSE treated horses (Figure 2
F), with p value lower than 0.05, already starting, in two subjects, from, T31. Flexion test is a fundamental parameter for the assessment of the clinical condition of the joint, including the connected anatomical structures (ligaments and tendons) which are subjected to mechanical stress, because it is positive even in the absence of a manifest lameness. In fact, chronic arthropathies frequently do not show serious or evident continuous signs of limping; therefore, a well-executed flexion test in some cases can detect even silent joint problems. Considering the significance of the statistical analysis of the time profiles of the scores of the flexion test in comparison with T0, in combination with the clinical improvement for the sensitivity and amplitude of passive flexions, it is plausible to attribute to CSE an analgesic effect that remains constant over time, while the product is administered to the horse. The reduction of the pain response, which allows the horses to improve joint mobility, has also been confirmed by the trainers who indicated in the surveys, that the 30 g BID CSE treated animals exhibit more elastic movements, are more dynamic and tolerate prolonged physical exercise in comparison with T0.
The reasons why in the horse the best responses occurred with a dosage (30 g BID), that is about 10 times higher than that recommended for humans remains to be defined; nevertheless, it can be hypothesized that it might reflect the different diets and food process mechanisms that characterize the two species. The horse, being a herbivore, has a gut microbiome that is more oriented to the chemical transformation and metabolism of compounds of vegetal origin than that of humans, which are omnivorous. On this basis, it could be speculated that the different metabolic elaboration capacity of food components could determine, in the horse, a more quantitative and/or faster inactivation of the components that are supposed to be responsible for the anti-inflammatory properties of CSE. As previously observed both in experimental animals and humans, and confirmed here in the horse, a relevant advantage of CSE in comparison to conventional anti-inflammatory drugs, is that it can be prescribed for protracted treatments, without unwanted side effects. In fact, both laboratory and clinical data form the present investigation showed that the health conditions of the animals didn’t change over a 59 days treatment. The most dangerous side effects of NSAIDs is the induction of ulcers in the gastrointestinal tract that, in the case of high dosages and prolonged treatments, can be detected by hypoalbuminemia and clinically evident edematous conditions, that were not found in the horses treated with CSE. The lack of side effects of a product like CSE, whose anti-inflammatory/analgesic properties are considered to be the same that characterize NSAIDs, certainly represents an intriguing issue. The answer to this question, could probably reside in the different delivery, turnover, and inhibitory activities for COX and LOX of the bioactive components of the CSE and NSAIDs in-vivo. Since the anti-inflammatory activity of CSE is probably determined by a mixture of bioactive compounds, their relative concentrations, synergies or mutual inhibition should be probably considered to understand the differences with NSAIDs. A possible answer to the lack of gastrolesivity by CSE, as mentioned above [14
], could be due to its gastroprotective effect, mediated through non-prostaglandin mechanisms.
Moreover, the lack of interference on cytochrome P450 activity reported in the literature for the murine and human species [28
], would represent a further index on the safety of the use of CSE also in equine medicine. In conclusion, although preliminary, the results presented here have shown on one side the analgesic properties of CSE in horses affected by OA, as well its possible application for prolonged treatments. Nevertheless it must be underlined that a larger number of treated subjects, as well as other variables which here have not been considered, like clinical severity, age, type of nutrition, attitude, type of pathology that gave rise to the OA status, the use of instrumental diagnostic tools for a more accurate monitoring of the clinical conditions of the animals, will be certainly necessary to better define protocols for its effective applications in equine orthopedics.