Acute ampakines increase voiding function and coordination in a rat model of SCI

Abstract

Neurogenic bladder dysfunction causes urological complications and reduces the quality of life in persons with spinal cord injury (SCI). Glutamatergic signaling via AMPA receptors is fundamentally important to the neural circuits controlling bladder voiding. Ampakines are positive allosteric modulators of AMPA receptors that can enhance the function of glutamatergic neural circuits after SCI. We hypothesized that ampakines can acutely stimulate bladder voiding that has been impaired due to thoracic contusion SCI. Adult female Sprague Dawley rats received a unilateral contusion of the T9 spinal cord (n=10). Bladder function (cystometry) and coordination with the external urethral sphincter (EUS) were assessed five days post-SCI under urethane anesthesia. Data were compared to responses in spinal intact rats (n=8). The low impact ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (HPCD) was administered intravenously. The HPCD vehicle had no discernable impact on voiding. In contrast, following CX1739, the pressure threshold for inducing bladder contraction, voided volume and the interval between bladder contractions were significantly reduced. These responses occurred in a dose-dependent manner. We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder voiding capability at sub-acute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.

Low-Impact Ampakine CX1739 Exerts Pro-Cognitive Effects and Reverses Opiate-Induced Respiratory Depression in Rodents

“…To enhance therapeutic gains, it has been described recently that low-impact ampakines can enhance respiratory neuroplasticity induced by acute intermittent hypoxia [25]. Furthermore, also in the setting of spinal cord injury, ampakines have been shown to increase voiding function and coordination [30]. It is becoming evident that in multiple neurological disease settings, AMPAR-positive allosteric modulation may yield significant benefits to patients with wide ranging symptomatologies.…”

“…Additional work has suggested the utility of ampakines to treat symptoms of major depressive disorder, for which development is ongoing in the pharmaceutical industry [27]. Current work on these compounds has been focused on respiratory insufficiency due to opioids [28,29] and to spinal cord injury and on the impairment in bladder function after spinal cord injury [30,31]. RespireRx Pharmaceuticals is actively engaged in developing these ampakine assets for these and other neurological and psychiatric disorders.…”