Sphenopalatine Ganglion Stimulation Upregulates Transport of Temozolomide across the Blood-Brain Barrier

Thana Theofanis ,Lorraine Iacovitti,Gagan Kaushal,Robert H Rosenwasser,Ankit Rochani ,Richard F Schmidt,Michael J Lang,Geoffrey Stricsek ,Ashwini Sharan

doi:10.3390/scipharm88030040

Abstract

Sphenopalatine ganglion (SPG) stimulation has been shown to reversibly alter blood-brain barrier (BBB) permeability. It is widely used for the treatment of cluster headaches in Europe and is well tolerated in humans. The therapeutic potential for SPG stimulation in other central nervous system (CNS) diseases has yet to be explored. Glioblastoma Multiforme (GBM) remains one of the most difficult primary CNS neoplasms to treat, with an average survival of approximately 18 months at the time of diagnosis. Since 2004, the gold standard of treatment for GBM in the United States includes surgery followed by treatment with temozolomide (TMZ) and radiation. We sought to determine if SPG stimulation could increase chemotherapy concentrations in rodent brains with an intact BBB. Here, we show a statistically significant (p = 0.0006), five-fold upregulation of TMZ crossing the BBB and reaching brain parenchyma in rats receiving low-frequency (LF, 10 Hz) SPG stimulation. All the measurements were performed using a highly sensitive liquid chromatography mass spectrometry (LCMS) method that was developed for quantitation of TMZ in plasma and brain tissue. Our treatment paradigm shows novel delivery route by which we could more effectively and safely deliver TMZ in a targeted manner, to minimize systemic toxicity and maximize action at the target tissue.

Highlights

The blood-brain barrier (BBB) remains an extremely challenging hurdle to therapeutic agents targeted for the central nervous system (CNS) [1,2]
Temozolomide (TMZ) is an important drug that is commonly explored for Glioblastoma Multiforme (GBM) therapy
Sphenopalatine ganglion (SPG) stimulation has been one of the major techniques that have played an important role in the reversible opening of BBB

Summary

Introduction

The blood-brain barrier (BBB) remains an extremely challenging hurdle to therapeutic agents targeted for the central nervous system (CNS) [1,2]. Sphenopalatine ganglion (SPG) stimulation is a novel approach to modulate BBB permeability in a targeted and transient manner [6,7,8]. The SPG is a parasympathetic ganglion found in the pterygopalatine fossa. It is largely innervated by the greater petrosal nerve (a branch of the facial nerve). SPG stimulation is used in humans for the treatment of cluster headaches, with trials showing safety and efficacy of an implantable microstimulator in the pterygopalatine fossa for this purpose [10,11,12]

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