Ampakines Stimulate Diaphragm Activity after Spinal Cord Injury

Rana, Sabhya; Sunshine, Michael D.; Greer, John J.; Fuller, David D.

doi:10.1089/neu.2021.0301

Cited by 22 publications

(19 citation statements)

References 44 publications

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“…The 45 min window allowed for the procedure to remain under ~6 hours. Further, in our published studies investigating the impact of ampakines on breathing in rats following an SCI, the acute impact of intravenous ampakine administration wanes after approximately 30 minutes (Rana et al, 2021) Thus, the dosing schedule was based on three factors: 1) the drug ½ life; 2) the duration of which the experimental preparation was viable, and 3) data from the respiratory response of ampakines after SCI.…”

Section: Chemical and Pharmacological Agentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The AMPA receptor can be allosterically modulated using pharmacologic compounds called ampakines (Arai and Kessler, 2007), and recent work suggests that these compounds have therapeutic value after SCI (Rana et al, 2021; Wollman et al, 2020). For example, when given after acute or chronic SCI in rats, ampakines have a powerful, beneficial impact on the glutamatergic synaptic pathways, which control breathing (Rana et al, 2021; Wollman et al, 2020). After high cervical SCI, diaphragm output is diminished, but systemically providing a low dose of ampakine can cause a rapid and sustained increase in diaphragm electromyogram output (Rana et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…For example, when given after acute or chronic SCI in rats, ampakines have a powerful, beneficial impact on the glutamatergic synaptic pathways, which control breathing (Rana et al, 2021; Wollman et al, 2020). After high cervical SCI, diaphragm output is diminished, but systemically providing a low dose of ampakine can cause a rapid and sustained increase in diaphragm electromyogram output (Rana et al, 2021). Since depolarization of the phrenic motoneurons that innervate the diaphragm critically depends on AMPA receptor activation (Chitravanshi and Sapru, 1996; Fuller et al, 2022; Rana et al, 2019), ampakines are likely acting at least in part on spinal circuits to stimulate diaphragm output (Thakre et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Rana

Alom

Martinez

et al. 2023

Preprint

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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.

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Section: Chemical and Pharmacological Agentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Rana

Alom

Martinez

et al. 2023

Preprint

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Safety, Tolerability, and Pharmacokinetic Profile of the Low‐Impact Ampakine CX1739 in Young Healthy Volunteers

Radin,

Cerne,

Witkin

et al. 2024

Clinical Pharm in Drug Dev

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AMPA‐type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the mammalian brain. Ampakines, positive allosteric modulators of AMPAR, hold significant potential for the treatment of a wide range of neurological/neuropsychiatric disorders in which excitatory synaptic transmission is compromised. Low‐impact ampakines are a distinct subset of ampakines that accelerate channel opening yet minimally affect receptor desensitization, which may explain their lack of seizurogenic effects at therapeutic doses in preclinical models. CX1739 is a low‐impact ampakine that has shown efficacy in preclinical studies. The current clinical study examined the tolerability and pharmacokinetics of CX1739 in healthy male volunteers in a 2‐part study. Part A was a single dose escalation study (100‐1200 mg, 48 patients) and Part B was a multiple dose ascending study (300‐600 mg BID for 7‐10 days, 32 patients). CX1739 was well tolerated up to 900 mg once daily (QD) and 450 mg twice a day, with the prominent side effects being headache and nausea. Importantly, the half‐life of CX1739 was 6‐9 hours, and Tmax was 1‐5 hours. CX1739 Cmax and AUC were dose‐proportional. These findings thus set the stage for further explorations of this drug candidate in phase 2 clinical studies.

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AMPA receptors play an important role in the biological consequences of spinal cord injury: Implications for AMPA receptor modulators for therapeutic benefit

Witkin,

Radin,

Rana

et al. 2024

Biochemical Pharmacology

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Ampakines Stimulate Diaphragm Activity after Spinal Cord Injury

Cited by 22 publications

References 44 publications

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

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

Safety, Tolerability, and Pharmacokinetic Profile of the Low‐Impact Ampakine CX1739 in Young Healthy Volunteers

AMPA receptors play an important role in the biological consequences of spinal cord injury: Implications for AMPA receptor modulators for therapeutic benefit

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