A Pneumatic-based Mechanism for Inserting a Flexible Microprobe into the Brain

Insertion of flexible microprobes into the brain requires withstanding the compressive penetration force by the microprobes. To aid the insertion of the microprobes, most of the existing approaches employ pushing mechanisms to provide temporary stiffness increase for the microprobes to prevent buckling during insertion into the brain. However, increasing the microprobe stiffness may result in acute neural tissue damage during insertion. Moreover, any late or premature removal of the temporary stiffness after insertion may lead to further tissue damage due to brain micromotion, or inaccuracy in the microprobe positioning. In this study, a novel pneumatic-based insertion mechanism is proposed which simultaneously pulls and pushes a flexible microprobe towards the brain. As part of the brain penetration force in the proposed mechanism is supplied by the tensile force, the applied compressive force, which the microprobe must withstand during insertion, is lower compared to the existing approaches. Therefore, the microprobes with a critical buckling force less than the brain penetration force can be inserted into the brain without buckling. Since there is no need for temporary stiffness increment, the neural tissue damage during the microprobe insertion will be much lower compared to the existing insertion approaches. The pneumatic-based insertion mechanism is modelled analytically to investigate the effects of the microprobe configuration and the applied air pressure on the applied tensile and compressive forces to the microprobe. Next, finite element modelling is conducted, and its analysis results not only validate the analytical results but also confirm the efficiency of the mechanism.

Olivetolic acid, a cannabinoid precursor in Cannabis sativa, but not CBGA methyl ester exhibits a modest anticonvulsant effect in a mouse model of Dravet syndrome

Objective Cannabigerolic acid (CBGA), a precursor cannabinoid in Cannabis sativa, has recently been found to have anticonvulsant properties in the Scn1a+/- mouse model of Dravet syndrome. Poor brain penetration and chemical instability of CBGA limits its potential as an anticonvulsant therapy. Here, we examined whether CBGA methyl ester, a more stable analogue of CBGA, might have superior pharmacokinetic and anticonvulsant properties. In addition, we examined whether olivetolic acid, the biosynthetic precursor to CBGA with a truncated (des-geranyl) form, might possess minimum structural requirements for anticonvulsant activity. We also examined whether olivetolic acid and CBGA methyl ester retain activity at the epilepsy-relevant drug targets of CBGA: G-protein-coupled receptor 55 (GPR55) and T-type calcium channels. Methods The brain and plasma pharmacokinetic profiles of CBGA methyl ester and olivetolic acid were examined following 10 mg/kg intraperitoneal (i.p.) administration in mice (n = 4). The anticonvulsant potential of each was examined in male and female Scn1a+/- mice (n = 17–19) against hyperthermia-induced seizures (10–100 mg/kg, i.p.). CBGA methyl ester and olivetolic acid were also screened in vitro against T-type calcium channels and GPR55 using intracellular calcium and ERK phosphorylation assays, respectively. Results CBGA methyl ester exhibited relatively limited brain penetration (13%), although somewhat superior to that of 2% for CBGA. No anticonvulsant effects were observed against thermally induced seizures in Scn1a+/- mice. Olivetolic acid also showed poor brain penetration (1%) but had a modest anticonvulsant effect in Scn1a+/- mice increasing the thermally induced seizure temperature threshold by approximately 0.4°C at a dose of 100 mg/kg. Neither CBGA methyl ester nor olivetolic acid displayed pharmacological activity at GPR55 or T-type calcium channels. Conclusions Olivetolic acid displayed modest anticonvulsant activity against hyperthermia-induced seizures in the Scn1a+/- mouse model of Dravet syndrome despite poor brain penetration. The effect was, however, comparable to the known anticonvulsant cannabinoid cannabidiol in this model. Future studies could explore the anticonvulsant mechanism(s) of action of olivetolic acid and examine whether its anticonvulsant effect extends to other seizure types.

Preclinical Data with KIT D816V Inhibitor Bezuclastinib (CGT9486) Demonstrates High Selectivity and Minimal Brain Penetrance

The molecular pathogenesis of Systemic Mastocytosis (SM) is driven by mutations in the KIT gene, with 95% of patients having a mutation in exon 17, D816V, leading to constant proliferation of mast cells (Garcia-Montero et al, 2006; Jara-Acevedo et al, 2015; Vaes et al, 2017). Targeted therapeutics have revealed clinical activity in these patients, but toxicities such as cognitive effects, intracranial hemorrhage, hypertension, and edema may limit dosing and availability of these therapies. While the exact cause of these effects is difficult to determine, numerous closely related kinases, such as wild type PDGFRα, PDGFRβ, KIT, VEGFR2 (KDR), and CSF1R (FMS), are considered to be anti-targets, with previous evidence of their inhibition linked to observed clinical toxicities (Liu & Kurzrock, 2015; Giles et al., 2009; Jayson et al., 2005). Bezuclastinib (CGT9486) was designed to selectively inhibit KIT D816V versus these other closely related kinase anti-targets. Additionally, we demonstrate that bezuclastinib has minimal brain penetration, together with no observed CNS-related toxicities in nonclinical studies. Herein, we present results from cell-based kinase profiling assays, which demonstrate that bezuclastinib has a significant and unique selectivity to KIT D816V relative to the aforementioned kinases when tested head-to-head against other clinically relevant compounds in SM. Additionally, a similar selectivity profile was observed for a broader panel of kinases, ion channels, transporters, and enzymes, which will be presented here, including drug concentrations and target engagement achieved with recent in vivo studies. Importantly, we also show that bezuclastinib has minimal brain penetration, a preferred feature of an anti-Kit molecule due to CNS-related adverse events observed in these indications. In a tissue distribution study performed in rats, bezuclastinib shows a brain:plasma ratio <0.1 following 3 day administration at 25 mg/kg, a dose that closely correlates with clinical plasma exposure. This was supported functionally by assessing neurobehavioral effects of bezuclastinib at dose levels up to 100 mg/kg in rats which showed no CNS related effects. This attractive selectivity and nonclinical safety profile, combined with early clinical data in advanced solid tumors (Trent et al, 2020), supports the potential for a best-in-class KIT inhibitor. Bezuclastinib is currently under clinical investigation in advanced SM with additional clinical studies planned in non-advanced SM and imatinib-resistant GIST. Disclosures Guarnieri: Cogent Biosciences: Current Employment. Cable: Cogent Biosciences: Current Employment. Bouhana: Cogent Biosciences: Current Employment. Sullivan: Cogent Biosciences: Current Employment. Ball: Cogent Biosciences: Current Employment. Sachs: Cogent Biosciences: Current Employment. Winski: Cogent Biosciences: Current Employment. Robinson: Cogent Biosciences: Current Employment.

Modern Phineas Gage: A Man with a Knife in the Brain

An accident with a tamping iron made Phineas Gage a historically famous brain-injury survivor. (1) Each year, approximately 1.6 million people sustain traumatic brain injury, leading to 52,000 deaths annually. (2) However, there is limited literature regarding traumatic brain penetration injury that could be found. A 42-year-old male with psychosis forcefully inserted a butter knife through nostril, traversed via sella turcica into posterior corpus callosum in a mental health facility. He was intubated in his local hospital and transferred over to a tertiary hospital for neurosurgical intervention. Radiological imaging showed impingement of knife against the posterior cerebral artery (PCA), multiple brain infarcts, intraventricular, and subarachnoid haemorrhage. The knife was removed after securing the PCA with the collaboration between neurosurgery and interventional radiology team. Sinus repair was immediately performed by the otorhinolaryngologists. External ventricular drain was inserted due to hydrocephalus secondary to brain haemorrhage. He eventually developed ventriculitis leading to sepsis and was treated with multiple antibiotics. The traumatic brain injury led to anterior hypopituitarism and diabetes insipidus which was treated using hormone therapy. He not only survived the fatal brain injury but also regained his Glasgow Coma Scale (GCS) score. This case demonstrates the potential of a multi-disciplinary and specialty approach to achieve outcomes a single specialty team could not. The outcome of a case which was deemed to be a non-survivable brain injury was made different due to the bold decision making, experience and innovative surgical strategy. Future research is needed to better understand and manage brain penetration injury.International Journal of Human and Health Sciences Supplementary Issue-2: 2021 Page: S27