Intranasally administered IGF-1 inhibits spreading depression in vivo

Abstract

Spreading depression (SD) is a wave of cellular depolarization that travels slowly through susceptible gray matter brain areas. SD is the most likely cause of migraine aura and perhaps migraine pain, and is a well-accepted animal model of migraine. Identification of therapeutics that can prevent SD may have clinical relevance toward migraine treatment. Here we show that insulin-like growth factor-1 (IGF-1) significantly inhibited neocortical SD in vivo after intranasal delivery to rats. A single dose of IGF-1 inhibited SD within an hour, and continued to protect for at least seven days thereafter. A two-week course of IGF-1, administered every third day, further decreased SD susceptibility and showed no aberrant effects on glial activation, nasal mucosa, or serum markers of toxicity. SD begets SD in vitro by mechanisms that involve microglial activation. We add to this relationship by showing that recurrent SD in vivo increased susceptibility to subsequent SD, and that intervention with IGF-1 significantly interrupted this pathology. These findings support nasal administration of IGF-1 as a novel intervention capable of mitigating SD susceptibility, and as a result, potentially migraine.

IFNγ-stimulated dendritic cell extracellular vesicles can be nasally administered to the brain and enter oligodendrocytes

“…Adequacy and consistency of anesthesia in spontaneously breathing animals was monitored by noting: 1) arterial oxygen tension that was kept between 95-100 mm Hg; 2) pink skin color in appendages; 3) regular respirations; and 4) absence of withdrawal to hind paw pinch [16,17]. Animals were placed in a supine position, and 50 μL of EVs in phosphate buffered saline (PBS; 100 μg protein) were administered over a 20 minute period at a rate of five μL every two minutes to alternating nostrils [6,13,18,19]. Sham animals were administered 50 μL of a vehicle (PBS, exosome-depleted culture medium/dye preparations, Unstim-DC-EVs or non-transfected IFNγ-DC-EVs as noted below in specific experiments).…”

IFNγ-Stimulated Dendritic Cell Exosomes for Treatment of Migraine Modeled Using Spreading Depression

“…The injection volume was calculated by measuring the injection sphere diameter in oil with a calibrated eye-piece micrometer on a compound microscope. As previously noted (Grinberg et al, 2017), injection volumes measured from injection into machine oil likely do not fully reflect injections made in vivo (Nicholson, 2001). However, any discrepancies would not be consequential as they would be a systemic error that would be equally applied to all experimental conditions.…”

“…For KCl-induced SD threshold measurements, a microelectrode with tip broken to 8–12 μm (1.0 mm outside diameter, 0.58 mm inside diameter; Sutter Lambda SC, Novato, CA, United States) and filled with 0.5 M KCl was positioned 750 μm below the pial surface at the anterior craniotomy. Micro-injections of KCl were administered via pressure from a Picospritzer-II electronic valve system (Parker Hannifin, Hollis, NH, United States), whose injection periods were registered directly to the permanent digital recording of interstitial DC potential changes (Grinberg et al, 2017). Injections of KCl were doubled in duration every four-to-five minutes if the previous injection failed to elicit an SD.…”

“…We found that exposure to an EE paradigm significantly reduces SD susceptibility in rats (Pusic K. M. et al, 2014). Mimicking the cytokine signaling of EE through administration of interleukin-11, insulin-like growth factor-1 or phasic administration of IFNγ likewise reduced susceptibility to SD (Pusic K. M. et al, 2014; Pusic and Kraig, 2015; Grinberg et al, 2017).…”

Design and Application in Delivery System of Intranasal Antidepressants

“…However, low residence time of drugs in the nasal cavity would affect absorption and in turn bioavailability of the drug, which has been a crucial problem that must be faced in clinical treatment. That is, the anatomic and physiologic characteristics of nasal mucosa must be considered in the design of nasal dosage forms used for solving the rapid mucocilliary clearance (MCC) (Grinberg et al, 2017 ; Patel and Patel, 2017 ; Li S. et al, 2018 ; Jiang et al, 2019 ; Qiu et al, 2020 ). Gel as a nasal mucoadhesive has been very attractive due to its fluid-like qualities prior to nasal administration and can easily be administered by drops to allow for accurate drug dosing.…”