Preclinical In-Vivo Safety of a Novel Thyrotropin-Releasing Hormone-Loaded Biodegradable Nanoparticles After Intranasal Administration in Rats and Primates.

Thyrotropin-releasing hormone (TRH) and TRH-like peptides carry a therapeutic potential for neurological conditions. Nanoparticles (NP) made of the biodegradable polymer, Poly(Sebacic Anhydride) (PSA), have been developed to carry TRH, intended for intranasal administration to patients. There is limited information on the safety of biodegradable polymers when given intranasally, and therefore, we have performed two preclinical safety and toxicity studies in cynomolgus monkeys and rats using TRH-PSA nanoparticles.

Intranasal delivery of neuropeptides.

A major barrier to entry of neuropeptides into the brain is low bioavailability and presence of the blood-brain barrier. Intranasal delivery of neuropeptides provides a potentially promising alternative to other routes of administration, since a direct pathway exists between the olfactory neuroepithelium and the brain. Use of the rat as an animal model in nose to brain delivery of neuropeptides allows for several advantages, including a large surface area within the nasal cavity dedicated to olfactory epithelium and robust neuronal pathways extending to and from most areas of the brain from the nose via the olfactory cortex.

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

Thyrotropin-releasing hormone (TRH) is reported to have anticonvulsant effects in animal seizure models and certain intractable epileptic patients. However, its duration of action is limited by rapid tissue metabolism and the blood brain barrier. Direct nose-brain delivery of neuropeptides in sustained-release biodegradable nanoparticles (NPs) is a promising mode of therapy for enhancing CNS bioavailability.

Attenuation of kindled seizures by intranasal delivery of neuropeptide-loaded nanoparticles.

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-to-brain delivery of neuropeptides in sustained-release biodegradable nanoparticles (NPs) is a promising mode of therapy for enhancing CNS neuropeptide bioavailability.

Isoflurane exacerbates electrically evoked seizures in amygdala-kindled rats during recovery.

Neuroexcitatory effects of isoflurane during or following anesthesia are controversial, particularly in epileptic patients. In contrast, halothane is generally considered to be highly anticonvulsant. Kindling is an animal model of epilepsy suitable for studying the effects of anesthetic agents on the epileptic brain.

Intranasal delivery of a thyrotropin-releasing hormone analog attenuates seizures in the amygdala-kindled rat.

Purpose: Thyrotropin-releasing hormone (TRH) is known to have anticonvulsant effects in several animal seizure models and is efficacious in treating patients with certain intractable epilepsies. However, the duration of TRH's action is limited due to low bioavailability and difficulty penetrating the blood-brain barrier (BBB). Since direct nose to brain delivery of therapeutic compounds may provide a means for overcoming these barriers, we utilized the kindling model of temporal lobe epilepsy to determine if intranasal administration of a TRH analog, 3-methyl-histidine TRH (3Me-H TRH), could significantly inhibit various seizure parameters.

An analog of thyrotropin-releasing hormone (TRH) is neuroprotective against glutamate-induced toxicity in fetal rat hippocampal neurons in vitro.

TRH has been found to be efficacious in treating certain neurodegenerative disorders such as epilepsy, Alzheimer's disease, neurotrauma and depression, however, its mechanism of action is poorly understood. Since glutamate (Glu) toxicity has been implicated in these disorders, we utilized primary enriched cultures of rat fetal (E 17) hippocampal neurons to test the hypothesis that an analog of TRH, 3-Methyl-Histidine TRH (3Me-H TRH), given concurrently with Glu would protect such neurons against cell damage and cell death. Cell viability was assessed via Trypan Blue exclusion cell counts, and neuronal damage was determined by assaying lactic acid dehydrogenase (LDH) released in the conditioned media.

Impaired growth and neurological abnormalities in branched-chain alpha-keto acid dehydrogenase kinase-deficient mice.

The BCKDH (branched-chain alpha-keto acid dehydrogenase complex) catalyses the rate-limiting step in the oxidation of BCAAs (branched-chain amino acids). Activity of the complex is regulated by a specific kinase, BDK (BCKDH kinase), which causes inactivation, and a phosphatase, BDP (BCKDH phosphatase), which causes activation. In the present study, the effect of the disruption of the BDK gene on growth and development of mice was investigated.

Thyrotropin-releasing hormone in the treatment of intractable epilepsy.

Intractable seizures remain a significant therapeutic challenge despite current advances in the treatment of epilepsy. Thyrotropin-releasing hormone, the first neuroendocrine releasing factor to be isolated and fully characterized, was also the first releasing factor investigated as a possible neurotransmitter/neuromodulator outside the hypothalamus. Basic and clinical research has revealed a distinct neuroanatomic distribution and a neurochemical role for thyrotropin-releasing hormone in seizure modulation.