Thyrotropin-releasing hormone d,l polylactide nanoparticles (TRH-NPs) protect against glutamate toxicity in vitro and kindling development in vivo

Veronesi, Michael C.; Aldouby, Yanir; Domb, Abraham J.; Kubek, Michael J.

doi:10.1016/j.brainres.2009.09.039

Cited by 39 publications

(21 citation statements)

References 54 publications

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“…30 In the same context, the use of PLA for encapsulation of TRH has been recently utilized with good results. 31 The success of polymeric nanoparticle formulation encouraged us to explore the encapsulation of TRH using PLGA nanoparticles (PLGA NPs) and to study the effect of such modification on the physicochemical nature of the resulting formulation. Hence, in this paper we report a nanoparticle system that will also help in improving the stability as the polymeric nanoparticles (PLGA) protect the peptide drug from proteolytic cleavage by enzymes and thereby help in achieving low drug dosage regime.…”

Section: Introductionmentioning

confidence: 99%

Thyrotropin-Releasing Hormone Loaded and Chitosan Engineered Polymeric Nanoparticles: Towards Effective Delivery of Neuropeptides

Kaur¹,

Bhararia²,

Sharma³

et al. 2016

j nanosci nanotechnol

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Thyrotropin-Releasing Hormone (TRH), a tripeptide amide with molecular formula L-pGlu-L-His-L- Pro-NH2, is used in the treatment of brain/spinal injury and certain central nervous system (CNS) disorders, including schizophrenia, Alzheimer's disease, epilepsy, depression, shock and ischemia due to its profound effects on the CNS. However, TRH's therapeutic activity is severely hampered because of instability and hydrophilicity owing to its peptidic nature which results into ineffective penetration into the blood brain barrier. In the present study, we report the synthesis and stability studies of novel chitosan engineered TRH encapsulated poly(lactide-co-glycolide) (PLGA) based nanoformulation. The aim of such an encapsulation is to allow effective delivery of TRH in biological systems as the peptidase degrade naked TRH. The synthesis of TRH was carried out manually in solution phase followed by its encapsulation using PLGA to form polymeric nanoparticles (NPs) via nanoprecipitation technique. Different parameters such as type of organic phase, concentration of stabilizer, ratio of organic phase and aqueous phase, rate of addition of organic phase were optimized, tested and evaluated for particle size, encapsulation efficiency, and stability of NPs. The TRH-PLGA NPs were then surface modified with chitosan to achieve positive surface charge rendering them potential membrane penetrating agents. PLGA, PLGA-TRH, Chitosan-PLGA and Chitosan-PLGA-TRH NPs were characterized and analyzed using Dynamic Light Scattering (DLS), Transmissiom Electron Microscopy (TEM) and Infra-red spectroscopic techniques.

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Section: Introductionmentioning

confidence: 99%

Thyrotropin-Releasing Hormone Loaded and Chitosan Engineered Polymeric Nanoparticles: Towards Effective Delivery of Neuropeptides

Kaur¹,

Bhararia²,

Sharma³

et al. 2016

j nanosci nanotechnol

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“…19 Some preliminary studies using nanoparticles like liposomes and polymers to encapsulate antiepileptic agents have shown anticonvulsive effects in epilepsy models. [20][21][22] However, these studies still use inert nanocarriers without biological activity, which may affect their efficacy in P-gp mediated drug-resistant epilepsy. In addition, some of these studies still used delivery of drugloaded nanoparticles via invasive routes, eg, local intracerebral implantation.…”

Section: Introductionmentioning

confidence: 99%

Enhanced brain delivery of lamotrigine with Pluronic® P123-based nanocarrier

Liu¹,

Wang²,

Zhou³

et al. 2014

IJN

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Background P-glycoprotein (P-gp) mediated drug efflux across the blood–brain barrier (BBB) is an important mechanism underlying poor brain penetration of certain antiepileptic drugs (AEDs). Nanomaterials, as drug carriers, can overcome P-gp activity and improve the targeted delivery of AEDs. However, their applications in the delivery of AEDs have not been adequately investigated. The objective of this study was to develop a nano-scale delivery system to improve the solubility and brain penetration of the antiepileptic drug lamotrigine (LTG). Methods LTG-loaded Pluronic ® P123 (P123) polymeric micelles (P123/LTG) were prepared by thin-film hydration, and brain penetration capability of the nanocarrier was evaluated. Results The mean encapsulating efficiency for the optimized formulation was 98.07%; drug-loading was 5.63%, and particle size was 18.73 nm. The solubility of LTG in P123/LTG can increase to 2.17 mg/mL, making it available as a solution. The in vitro release of LTG from P123LTG presented a sustained-release property. Compared with free LTG, the LTG-incorporated micelles accumulated more in the brain at 0.5, 1, and 4 hours after intravenous administration in rats. Pretreatment with systemic verapamil increased the rapid brain penetration of free LTG but not P123/LTG. Incorporating another P-gp substrate (Rhodamine 123) into P123 micelles also showed higher efficiency in penetrating the BBB in vitro and in vivo. Conclusion These results indicated that P123 micelles have the potential to overcome the activity of P-gp expressed on the BBB and therefore show potential for the targeted delivery of AEDs. Future studies are necessary to further evaluate the appropriateness of the nanocarrier to enhance the efficacy of AEDs.

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“…Nonetheless, we believe that these are the first data to appear that provide direct proof of concept for efficacy in the use of intranasal biodegradable nanoparticle seizure therapy. 65,66 Taken together, our results strongly suggest that intranasal administration of sustained-release anticonvulsant neuropeptide nanoparticles may be a viable new means for suppressing temporal lobe seizures and other intractable seizures, such as West syndrome and Lennox-Gastaut syndrome.…”

Section: Effect Of Intranasal Delivery Of Trh Nanoparticles On Kindlimentioning

confidence: 69%

Attenuation of Kindled Seizures by Intranasal Delivery of Neuropeptide-Loaded Nanoparticles

2009

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Summary: Thyrotropin-releasing hormone (TRH; Protirelin), an endogenous neuropeptide, is known to have anticonvulsant effects in animal seizure models and certain intractable epileptic patients. Its duration of action, however, is limited by rapid tissue metabolism and the blood-brain barrier. Direct nose-tobrain delivery of neuropeptides in sustained-release biodegradable nanoparticles (NPs) is a promising mode of therapy for enhancing CNS neuropeptide bioavailability. To provide proof of principle for this delivery approach, we used the kindling model of temporal lobe epilepsy to show that 1) TRH-loaded copolymer microdisks implanted in a seizure focus can attenuate kindling development in terms of behavioral stage, afterdischarge duration (ADD), and clonus duration; 2) intranasal administration of an unprotected TRH analog can acutely suppress fully kindled seizures in a concentration-dependent manner in terms of ADD and seizure stage; and 3) intranasal administration of polylactide nanoparticles (PLA-NPs) containing TRH (TRH-NPs) can impede kindling development in terms of behavioral stage, ADD, and clonus duration. Additionally, we used intranasal delivery of fluorescent dye-loaded PLA-NPs in rats and application of dye-loaded or dye-attached NPs to cortical neurons in culture to demonstrate NP uptake and distribution over time in vivo and in vitro respectively. Also, a nanoparticle immunostaining method was developed as a procedure for directly visualizing the tissue level and distribution of neuropeptide-loaded nanoparticles. Collectively, the data provide proof of concept for intranasal delivery of TRH-NPs as a viable means to 1) suppress seizures and perhaps epileptogenesis and 2) become the lead compound for intranasal anticonvulsant nanoparticle therapeutics.

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Thyrotropin-releasing hormone d,l polylactide nanoparticles (TRH-NPs) protect against glutamate toxicity in vitro and kindling development in vivo

Cited by 39 publications

References 54 publications

Thyrotropin-Releasing Hormone Loaded and Chitosan Engineered Polymeric Nanoparticles: Towards Effective Delivery of Neuropeptides

Thyrotropin-Releasing Hormone Loaded and Chitosan Engineered Polymeric Nanoparticles: Towards Effective Delivery of Neuropeptides

Enhanced brain delivery of lamotrigine with Pluronic® P123-based nanocarrier

Attenuation of Kindled Seizures by Intranasal Delivery of Neuropeptide-Loaded Nanoparticles

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Thyrotropin-releasing hormone d,l polylactide nanoparticles (TRH-NPs) protect against glutamate toxicity in vitro and kindling development in vivo

Cited by 39 publications

References 54 publications

Thyrotropin-Releasing Hormone Loaded and Chitosan Engineered Polymeric Nanoparticles: Towards Effective Delivery of Neuropeptides

Thyrotropin-Releasing Hormone Loaded and Chitosan Engineered Polymeric Nanoparticles: Towards Effective Delivery of Neuropeptides

Enhanced brain delivery of lamotrigine with Pluronic&reg; P123-based nanocarrier

Attenuation of Kindled Seizures by Intranasal Delivery of Neuropeptide-Loaded Nanoparticles

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Product

Resources

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Enhanced brain delivery of lamotrigine with Pluronic® P123-based nanocarrier