a-surgical-approach-for-optic-nerve-crush-in-a-rabbit-model

A Surgical Approach for Optic Nerve Crush in a Rabbit Model

Optic nerve crush (ONC) is an experimental technique used to model and study the mechanisms of optic neuropathies and potential therapeutic interventions. ...

Stanford University

The role of granule cell axon (mossy fiber) sprouting in temporal lobe epileptogenesis is unclear and controversial. Rapamycin suppresses mossy fiber sprouting, but its reported effects on seizure frequency are mixed. The present study used high-dose rapamycin to more completely block mossy fiber sprouting and to measure the effect on seizure frequency.

High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy.

Increased endoplasmic reticulum (ER) stress is one of the earliest subcellular changes in neuro-ophthalmic diseases. In this study, we investigated the expression of key molecules in the ER stress pathways following nonarteritic anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in adults over 50, and assessed the impact of chemical chaperon 4-phenylbutyric acid (4-PBA) in vivo.

Increased ER Stress After Experimental Ischemic Optic Neuropathy and Improved RGC and Oligodendrocyte Survival After Treatment With Chemical Chaperon.

Alfaxalone is an injectable anesthetic agent that is used in veterinary medicine for general anesthesia. We evaluated the safety and efficacy of alfaxalone delivered through continuous rate infusion by comparing ketamine-xylazine-alfaxalone (KXA) anesthesia with ketamine-xylazine (KX) anesthesia in Sprague-Dawley rats. Anesthesia was induced in male and female rats by using subcutaneous KX. After induction, rats in the KXA group received alfaxalone (10 mg/kg/h IV) for 35 min, whereas rats in the KX group did not receive alfaxalone. At the end of the trial, alfaxalone was discontinued, and xylazine was reversed in all rats by using atipamezole. Throughout anesthesia, we assessed forepaw withdrawal reflex (FPWR), hindpaw withdrawal reflex (HPWR), response to surgical stimulation, heart rate, respiratory rate, SpO₂, body temperature, and time to standing. KXA produced a reliable surgical plane of anesthesia, as evidenced by the loss of both FPWR and HPWR and lack of response to surgical stimulation in all 16 rats, whereas only 6 of the 16 rats in the KX group lost HPWR. No rat in the KXA group regained a paw withdrawal reflex during alfaxalone administration, whereas 3 of the 12 rats (25%) in the KX group that reached a surgical plane of anesthesia exited that plane within the 35-min timeframe. Neither heart rate, respiratory rate, SpO₂, body temperature, nor time to standing differed between KXA and KX groups; and there were no sex-associated differences in anesthesia response. These results indicate that alfaxalone (10 mg/kg/h IV) delivered through continuous rate infusion, in combination with ketamine and xylazine, provides a safe, prolonged, and reliable surgical plane of anesthesia in rats.

Continuous Rate Infusion of Alfaxalone during Ketamine-Xylazine Anesthesia in Rats.

Multiphoton microscopy can resolve fluorescent structures and dynamics deep in scattering tissue and has transformed neural imaging, but applying this technique in vivo can be limited by the mechanical and optical constraints of conventional objectives. Short working distance objectives can collide with compact surgical windows or other instrumentation and preclude imaging. Here we present an ultra-long working distance (20 mm) air objective called the Cousa objective. It is optimized for performance across multiphoton imaging wavelengths, offers a more than 4 mm field of view with submicrometer lateral resolution and is compatible with commonly used multiphoton imaging systems. A novel mechanical design, wider than typical microscope objectives, enabled this combination of specifications. We share the full optical prescription, and report performance including in vivo two-photon and three-photon imaging in an array of species and preparations, including nonhuman primates. The Cousa objective can enable a range of experiments in neuroscience and beyond.

The Cousa objective: a long-working distance air objective for multiphoton imaging in vivo.

Traumatic optic neuropathy (TON) is a devastating condition that can occur after blunt or penetrating trauma to the head, leading to visual impairment or blindness. Despite these debilitating effects, no clinically available therapeutic targets neuroprotection or promotes axon regeneration in this or any optic neuropathy. Limited data in large-animal models are a major obstacle to advancing treatments toward clinical therapeutics. To address this issue, we refined a surgical model of TON in Yucatan minipigs. First, we validated the model by demonstrating visual impairment by flash visual-evoked potential and retinal ganglion cell degeneration and death. Next, we developed and optimized a delivery method and nontoxic dosing of intravitreal brain-derived neurotrophic factor (BDNF) and cAMP. Finally, we showed that intravitreal injection of BDNF and cAMP rescued visual function and protected against retinal ganglion cell death and optic nerve axon degeneration. Together these data in a preclinical large-animal model advance our understanding of and ability to model TON and further identify and develop candidate clinical therapeutics.

BDNF and cAMP are neuroprotective in a porcine model of traumatic optic neuropathy.

Targeted drug delivery to the optic nerve head may be useful in the preclinical study and later clinical management of optic neuropathies, however, there are no FDA-approved drug delivery systems to achieve this. The purpose of this work was to develop an optic nerve head drug delivery technique.

Article	Year
High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy. Epilepsia\| PubMed ID: 23848506	2013
Increased ER Stress After Experimental Ischemic Optic Neuropathy and Improved RGC and Oligodendrocyte Survival After Treatment With Chemical Chaperon. Investigative ophthalmology & visual science\| PubMed ID: 31060051	2019
Continuous Rate Infusion of Alfaxalone during Ketamine-Xylazine Anesthesia in Rats. Journal of the American Association for Laboratory Animal Science : JAALAS\| PubMed ID: 32059754	2020
The Cousa objective: a long-working distance air objective for multiphoton imaging in vivo. Nature methods\| PubMed ID: 38129618	2024
BDNF and cAMP are neuroprotective in a porcine model of traumatic optic neuropathy. JCI insight\| PubMed ID: 38194296	2024
Development of a novel SupraChoroidal-to-Optic-NervE (SCONE) drug delivery system. Drug delivery\| PubMed ID: 39010743	2024

Kathleen Heng

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