Preclinical Evaluation of a Zotarolimus-Eluting Stent for Intracranial Application: A 30-Day GLP Canine Study

Bhatti, I. A.; Jumah, F.; Gillani, S. A.; Nunna, R.; Khan,, I.; Rolfes, A.; Jagadeesan, B. D.; Hassan, A. E.; Qureshi, A. I.; Siddiq, F.

doi:10.1101/2025.11.25.690612

bioRxiv · 10.1101/2025.11.25.690612

Preclinical Evaluation of a Zotarolimus-Eluting Stent for Intracranial Application: A 30-Day GLP Canine Study

Bhatti, I. A.·Jumah, F.·Gillani, S. A.·Nunna, R.·Khan,, I.·Rolfes, A.·Jagadeesan, B. D.·Hassan, A. E.·Qureshi, A. I.·Siddiq, F.

View original source ↗Export metadata ↓

Abstract

BackgroundZotarolimus-Eluting Stents (ZES) are increasingly used off-label for intracranial atherosclerotic disease (ICAD). However, foundational, Good Laboratory Practice (GLP) compliant preclinical safety data specific to the cerebral vasculature is lacking. Therefore, we conducted the first systematic evaluation of the technical feasibility, anatomic features, and 30-day clinical safety profile of the Onyx Frontier ZES (Medtronic, Minneapolis, MN) in a GLP-compliant canine intracranial model. MethodsIn a prospective GLP study, a 2.0 x 8.0 mm Onyx Frontier ZES was implanted in the basilar artery of twelve healthy mongrel canines pre-treated with dual antiplatelet therapy. Vertebral artery tortuosity was assessed via angiography and graded as Type I (non-tortuous/straight), Type II (moderately tortuous/S-shaped), or Type III (severely tortuous/coiled). The primary endpoints were procedural success and 30-day safety, assessed via angiography, serial neurological examinations, and comprehensive clinical monitoring. ResultsTechnical success was achieved in 100% of animals (12/12). The cohort exhibited challenging anatomy, with a mean basilar artery diameter of 1.39 {+/-} 0.10 mm. Tortuosity analysis revealed that 33.3% of animals were Type I (mild), 58.3% were Type II (moderate), and 8.3% were Type III (severe). Post-procedure, mild vasospasm was observed in all cases, with only one canine requiring intra-arterial verapamil. A single case (8.3%) of self-limiting contrast extravasation occurred without clinical sequelae. At 30 days, there was no mortality, and no animals suffered a neurological adverse event. Minor clinical events were unrelated to the device, and comprehensive clinical pathology panels revealed no evidence of systemic toxicity or a significant inflammatory response. ConclusionThis first-of-its-kind preclinical study demonstrates that implantation of the Onyx Frontier ZES is technically feasible with a 100% success rate in a sub-2mm vessel model with significant tortuosity and has an excellent 30-day safety profile with no clinical evidence of neurotoxicity. These findings provide foundational preclinical data supporting further investigation of this technology for treating ICAD in human subjects.

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Bhatti, I. A., Jumah, F., Gillani, S. A., Nunna, R., Khan,, I., Rolfes, A., Jagadeesan, B. D., Hassan, A. E., Qureshi, A. I., Siddiq, F.. 2025-11-30. Preclinical Evaluation of a Zotarolimus-Eluting Stent for Intracranial Application: A 30-Day GLP Canine Study. https://doi.org/10.1101/2025.11.25.690612

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Isogenic forebrain organoids uncover early neurodevelopmental alterations and imbalances in neuronal function leading to hyperexcitation in Gaucher disease

Gaucher disease is a rare lysosomal storage disorder caused by autosomal recessive mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase. Gaucher disease is classified in 3 different subtypes depending on the presence and severity of neurological involvement, with type 2 resulting in fatal early-onset neuropathology and patients exhibiting developmental delays, seizures and early death. Studies investigating disease mechanisms of neuronopathic Gaucher disease are mainly based on animal models and focus predominantly on late neuronal phenotypes. Here, we established healthy control and Gaucher disease patient-derived iPSC lines and engineered them to obtain isogenic control and disease lines. Using these lines, we generated cortical and subpallial brain organoids in which we identified early-onset lipid dysregulation in form of glucosylceramide accumulation, highly elevated glucosylsphingosine, and a later increase in ganglioside levels, recapitulating clinical findings. Furthermore, single-cell transcriptomic profiling uncovered novel phenotypes in both cortical and subpallial forebrain organoids. Subpallial alterations consisted of an early increase in migrating interneurons in subpallial organoids, which upregulated cholesterol metabolism. Cortical alterations showed early upregulation of mitochondrial genes and a downregulation of proliferation, with a subsequent switch from GABAergic to glutamatergic neuron fate with a striking increase in gene expression related to the synaptic assembly. Functional assays demonstrated a marked hyperexcitability of cortical organoids and reduced response to GABA-A receptor blockage in Gaucher disease. Additional 2D neuronal network models confirmed the organoid data and showed that both glutamatergic and GABAergic neurons contribute to the phenotype, with hyperexcitability of Gaucher glutamatergic neurons and incapacity of Gaucher GABAergic neurons to balance the excessive excitation. This alteration represents a clinically significant phenotype as many patients exhibit an excitation/inhibition imbalance leading to treatment-resistant seizures, hastening their decline. In conclusion, our defined human models of Gaucher disease identify novel and clear phenotypes that can be used for drug screening or aid in development of new therapeutic strategies to ameliorate Gaucher disease.

neuroscience↗

bioRxiv2026

Oxytocin and Vasopressin Immunoreactivity Differs Across Auditory Brainstem Nuclei in Rodents with Distinct Social Systems

Oxytocin (OT) and vasopressin (AVP) are neuropeptide hormones involved in regulating animal social behavior and a broad spectrum of physiological processes. Although their distributions are well documented in neuroendocrine regions of the forebrain and midbrain, their expression in the hindbrain remains poorly understood. Here, we used immunohistochemistry to quantify OT and AVP immunoreactive puncta within three auditory brainstem nuclei, the lateral superior olive (LSO), the medial superior olive (MSO), and the medial nucleus of the trapezoid body (MNTB) in six wild-caught rodent species differing in sociality. We also quantified the volume of these nuclei and examined variation in total brain volume across species and sociality. OT and AVP puncta count differed among species and social groups. Group-living species exhibited higher OT and AVP puncta counts than monogamous and solitary species in the LSO and MNTB. In the MSO, OT puncta counts did not differ among social groups, whereas AVP puncta counts were higher in group-living than in monogamous and solitary species. Total brain volume and the volumes of the MNTB and MSO differed among species, but not across social groups, whereas LSO volume did not differ among species or sociality. These findings revealed sociality-related variation in OT and AVP immunoreactive puncta within auditory brainstem circuits and suggest that neuropeptide signaling within early auditory brainstem pathways may contribute to the neural integration of social and auditory information.

neuroscience↗

bioRxiv2026

Connexin 40 deficiency alters the temporal profile of postictal oxygen dynamics following focal seizures.

Epilepsy is increasingly recognized as a disorder involving both neuronal and vascular dysfunction. While connexin signaling has been implicated in epileptogenesis, the contribution of vascular connexins to seizure associated cerebrovascular pathology remains poorly understood. Connexin40 (Cx40) is an endothelial gap junction protein that plays a crucial role in vascular communication and blood-flow regulation. Seizures induce dynamic changes in cerebral perfusion and oxygenation, including prolonged postictal hypoperfusion/hypoxia. To determine whether Cx40 influences postictal hypoxia following focal seizures, we examined seizure characteristics and postictal oxygen dynamics in Cx40 knockout (Cx40-/-) mice using an established focal hippocampal seizure model. Electrically kindled seizures were elicited in wild-type and Cx40-/- mice, and local hippocampal tissue oxygenation was continuously monitored before and after seizure induction. Seizure duration did not differ between genotypes, indicating comparable seizure severity. Interestingly, Cx40 deletion altered the temporal pattern of postictal oxygen recovery, producing greater early hypoxia and a delayed secondary rebound in pO2 despite similar peak oxygen levels and overall hypoxic burden. These findings demonstrate that loss of Cx40 selectively alters the temporal profile of postictal oxygen dynamics without affecting seizure duration. Taken together, the results suggest that endothelial gap junctional communication contributes to postictal vascular recovery and identify Cx40 as a potential modulator of seizure associated neurovascular dysfunction.

neuroscience↗