A preclinical study by NLS Pharmaceutics demonstrates that mazindol mitigates circadian activity disruption in a rat model with narcoleptic-like symptoms.


Summary: NLS Pharmaceutics Ltd will present a preclinical study at the ASCP conference showing that mazindol, administered at 3 mg/kg, mitigated circadian activity disruption in rats with narcoleptic-like symptoms induced by orexin-B-saporin lesions. The study found that mazindol restored and even exceeded normal activity levels, demonstrating neuroprotective effects. Lower doses were ineffective. The research suggests mazindol might modulate orexin receptors or pathways. These findings support further clinical development of mazindol for narcolepsy and related disorders. The study was led by Eric Konofal, chief scientific officer of NLS Pharmaceutics.

Key Takeaways:

  1. A preclinical study found that mazindol, administered at a dose of 3 mg/kg, mitigated circadian activity disruption and even exceeded normal activity levels in rats with narcoleptic-like symptoms.
  2. The study highlighted the importance of dosage, showing that lower doses of mazindol (1 mg/kg) were ineffective and could potentially worsen symptoms, while the higher dose (3 mg/kg) was beneficial.
  3. The research suggests that mazindol may exert its effects through modulation of orexin receptors or pathways, supporting further clinical development of mazindol for treating narcolepsy and related disorders.

Swiss clinical-stage biopharmaceutical company NLS Pharmaceutics Ltd will present results from a preclinical study showing potential benefits of mazindol for narcoleptic-like symptoms at the American Society of Clinical Psychopharmacology (ASCP) conference in Miami.

This study evaluated the neuroprotective effects of mazindol on nocturnal activity in a rat model with narcoleptic-like symptoms induced by orexin-B-saporin (OX-B-SAP) lesions in the lateral hypothalamus.

“These data underscore our continued commitment to advancing our pipeline which has the potential to change the treatment paradigm for patients impacted by sleep and wakefulness disorders and highlights the promise of mazindol to reduce the suffering of patients with narcolepsy,” says Eric Konofal, MD, PhD, chief scientific officer of NLS Pharmaceutics, in a release.

The poster presentation, “Neuroprotective effect of mazindol on nocturnal activity in an orexin-B-saporin-induced narcoleptic-like model in Sprague-Dawley rats,” will be presented by Konofal on May 30 from 12:30-2:15 pm EST.

Key Findings

Neuroprotective Efficacy: Mazindol, administered at a dose of 3 mg/kg, significantly mitigated the reduction in circadian activity typically induced by OX-B-SAP lesions. By day 21, mazindol not only restored activity levels to normal but exceeded those of the sham group during the dark phase, demonstrating a robust protective effect against orexin cell loss.

Dose-Dependent Response: The study highlighted the importance of dosage, as lower doses of mazindol (1 mg/kg) did not show therapeutic benefits and might have aggravated the decrease in activity between days five and eight post-lesion. Conversely, the higher dose (3 mg/kg) significantly increased circadian activity, indicating its potential utility in treating disorders like narcolepsy, where orexin system disruption leads to decreased wakefulness.

Orexinergic Mechanisms: The results suggest that mazindol might exert its effects through direct or indirect modulation of orexin receptors or pathways influenced by the orexin system. The lack of significant modification in the number of orexin neurons by mazindol treatment underscores the complex interaction between mazindol and orexin signaling.

Study Details

The study utilized Sprague-Dawley rats with OX-B-SAP lesions in the lateral hypothalamus to mimic narcoleptic symptoms. The primary objectives were to assess the extent of circadian activity disruption and evaluate the neuroprotective impact of mazindol. 

Key parameters included:

Circadian Activity Monitoring: Activity was recorded continuously, with significant findings showing that mazindol-treated rats exhibited higher activity levels during the dark phase compared to vehicle-treated rats.

Histological Analysis: The extent of orexin neuron loss was evaluated post-mortem, confirming the targeted lesioning by OX-B-SAP and the neuroprotective effect of mazindol.

Conclusion

The outcomes from study KO-874 support further clinical development of mazindol as a potential therapeutic for narcolepsy and other disorders involving orexin system disruption, according to a release from NLS Pharmaceutics. 

The company states it remains committed to advancing this compound through clinical trials to address unmet needs in sleep and wakefulness disorders.

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