Treatment of Rat Spinal Cord Injury with the Neurotrophic Factor Albumin-Oleic Acid: Translational Application for Paralysis, Spasticity and Pain

Abstract

Sensorimotor dysfunction following incomplete spinal cord injury (iSCI) is often characterized by the debilitating symptoms of paralysis, spasticity and pain, which require treatment with novel pleiotropic pharmacological agents. Previous in vitro studies suggest that Albumin (Alb) and Oleic Acid (OA) may play a role together as an endogenous neurotrophic factor. Although Alb can promote basic recovery of motor function after iSCI, the therapeutic effect of OA or Alb-OA on a known translational measure of SCI associated with symptoms of spasticity and change in nociception has not been studied. Following T9 spinal contusion injury in Wistar rats, intrathecal treatment with: i) Saline, ii) Alb (0.4 nanomoles), iii) OA (80 nanomoles), iv) Alb-Elaidic acid (0.4/80 nanomoles), or v) Alb-OA (0.4/80 nanomoles) were evaluated on basic motor function, temporal summation of noxious reflex activity, and with a new test of descending modulation of spinal activity below the SCI up to one month after injury. Albumin, OA and Alb-OA treatment inhibited nociceptive Tibialis Anterior (TA) reflex activity. Moreover Alb-OA synergistically promoted early recovery of locomotor activity to 50±10% of control and promoted de novo phasic descending inhibition of TA noxious reflex activity to 47±5% following non-invasive electrical conditioning stimulation applied above the iSCI. Spinal L4–L5 immunohistochemistry demonstrated a unique increase in serotonin fibre innervation up to 4.2±1.1 and 2.3±0.3 fold within the dorsal and ventral horn respectively with Alb-OA treatment when compared to uninjured tissue, in addition to a reduction in NR1 NMDA receptor phosphorylation and microglia reactivity. Early recovery of voluntary motor function accompanied with tonic and de novo phasic descending inhibition of nociceptive TA flexor reflex activity following Alb-OA treatment, mediated via known endogenous spinal mechanisms of action, suggests a clinical application of this novel neurotrophic factor for the treatment of paralysis, spasticity and pain.

Abnormal cutaneous flexor reflex activity during controlled isometric plantarflexion in human spinal cord injury spasticity syndrome

“…The reflex testing procedure developed here provides a useful technique to differentiate abnormal CR activity in subjects with clinical signs of SCI spasticity and could be used to benchmark novel pharmacological or sensorimotor rehabilitation techniques designed to re-establish appropriate inhibitory modulation of CR function, thereby contributing to the better management of SCI spasticity. 40,42,66,70 DATA ARCHIVING There were no data to deposit.…”

“…41,[61][62][63] Specifically, the alpha-2 adrenoceptor agonist clonidine has been shown not only to restore inhibition of CR activity after SCI but also to facilitate TA muscle activation during gait, 64 supporting the hypothesis that adequate CR control improves residual motor function. We believe that careful CR testing should be used to benchmark standard and new pharmacological strategies for the control of the SCI spasticity syndrome, 63,65,66 while examining the wider effect of these therapies on residual muscle function after SCI 40,41 Limitations and future studies No correlation was identified between Pl-TA CR activity and the grade of hypertonia or spasm frequency, perhaps reflecting the poor sensitivity of the modified Ashworth and Penn scales to detect flexor reflex activity. Measurement of spasm activity in clinical studies is usually performed with the Penn scale, 35 but this scale often fails to correlate with the underlying pathophysiological mechanisms of SCI spasticity syndrome during movement, 7 or indeed with CR activity in general.…”

Premature or pathological aging: longevity

“…Even when people are resting, some areas of the brain are activated simultaneously, pulsating at the same frequency, which suggests that groups of neurons are communicating. This network is less active in a person with Alzheimer's (BALTHAZAR et al, 2014). The Unicamp group was able to distinguish with about 70% accuracy the images of brain activity in resting people with moderate symptoms of dementia, typical of healthy older people.…”

“…However, in the short term it may be more realistic to think of ways to slow down the progress of brain injuries leading to Alzheimer's and prevent as much as possible the appearance of cognitive problems that gradually reduce the quality of life of patients. Details of the latest research on Alzheimer's mentioned above can be found in recent publications (MARTINS et al, 2005;MORI et al, 2008;ANDRADE-MORAES et al, 2013;LOURENÇO et al, 2013;BALTHAZAR et al, 2014).…”

“…The researchers also observed a relationship between network connection failures and degree of memory loss. According to Balthazar et al (2014), the earlier the diagnosis is more effective the interventions that relieve symptoms; use of acetylcholinesterase inhibitors and practice of occupational therapy, psychological rehabilitation and physical activity, as well as family planning for the future.…”