A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.

Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

Synthesis of α-Ketoglutaramic acid.

α-Ketoglutaramic acid (KGM, α-ketoglutaramate), also known as 2-oxoglutaramic acid (OGM, 2-oxoglutaramate), is a substrate of ω-amidase, also known as Nitrilase 2 (NIT2), and is essential for studying the canonical role of ω-amidase, as well as its role in multiple diseases. Until now, KGM used for biological studies has been prepared most often by the enzymatic oxidation of l-glutamine using snake venom l-amino acid oxidase, which provides KGM as an aqueous solution, containing by-products including 5-oxoproline and α-ketoglutarate. The enzymatic method for KGM preparation, therefore, cannot provide pure product or an accurate percent yield evaluation. Here, we report a synthetic method for the preparation of this important substrate, KGM, in 3 steps, from l-2-hydroxyglutaramic acid, in pure form, in 53% overall yield.

Multiple-step, one-pot synthesis of 2-substituted-3-phosphono-1-thia-4-aza-2-cyclohexene-5-carboxylates and their corresponding ethyl esters.

The multiple-step, one-pot procedure for a series of 2-substituted-3-phosphono-1-thia-4-aza-2-cyclohexene-5-carboxylates, analogues of the natural, sulfur amino acid metabolite lanthionine ketimine (LK), its 5-ethyl ester (LKE) and 2-substituted LKEs is described. Initiating the synthesis with the Michaelis-Arbuzov preparation of α-ketophosphonates allows for a wide range of functional variation at the 2-position of the products. Nine new compounds were synthesized with overall yields range from 40 to 62%. In addition, the newly prepared 2-isopropyl-LK-P, 2-n-hexyl-LKE-P and 2-ethyl-LKE were shown to stimulate autophagy in cultured cells better than that of the parent compound, LKE.

CTB-targeted protocells enhance ability of lanthionine ketenamine analogs to induce autophagy in motor neuron-like cells.

Impaired autophagy, a cellular digestion process that eliminates proteins and damaged organelles, has been implicated in neurodegenerative diseases, including motor neuron disorders. Motor neuron targeted upregulation of autophagy may serve as a promising therapeutic approach. Lanthionine ketenamine (LK), an amino acid metabolite found in mammalian brain tissue, activates autophagy in neuronal cell lines. We hypothesized that analogs of LK can be targeted to motor neurons using nanoparticles to improve autophagy flux. Using a mouse motor neuron-like hybrid cell line (NSC-34), we tested the effect of three different LK analogs on autophagy modulation, either alone or loaded in nanoparticles. For fluorescence visualization of autophagy flux, we used a mCherry-GFP-LC3 plasmid reporter. We also evaluated protein expression changes in LC3-II/LC3-I ratio obtained by western blot, as well as presence of autophagic vacuoles per cell obtained by electron microscopy. Delivering LK analogs with targeted nanoparticles significantly enhanced autophagy flux in differentiated motor neuron-like cells compared to LK analogs alone, suggesting the need of a delivery vehicle to enhance their efficacy. In conclusion, LK analogs loaded in nanoparticles targeting motor neurons constitute a promising treatment option to induce autophagy flux, which may serve to mitigate motor neuron degeneration/loss and preserve motor function in motor neuron disease.

Analysis of a Long-Standing Consultant Pharmacy Service in Home Health Care.

OBJECTIVE: To analyze the long-term utilization of an on-site consultant pharmacist referral service at a home health care (HHC) agency (HHA) and the medication-related problems in the homebound patients served.
DESIGN: A retrospective, descriptive study reporting the pharmacist's role in providing pharmaceutical care to patients referred by HHC clinicians from 2009 through 2015.
SETTING: A nonprofit HHA in Spokane, Washington, that has utilized a consultant pharmacist service for more than 20 years as part of an academic partnership with Washington State University.
PARTICIPANTS: All patients referred to the pharmacy team were eligible for inclusion in the data analysis.
INTERVENTIONS: Pharmacists provided comprehensive medication management via telephone calls, home visits, and communication with HHA clinicians to resolve clinician-referred problems.
MAIN OUTCOMES: Reason for referral, modality of resolution, number and type of medication-related problems, prescriber response rate.
RESULTS: Of 1,263 referrals, the pharmacy team resolved the case by visiting 421 patients, calling 261 patients, and collaborating with the clinician team for 323 patients; 258 patients declined or were lost to follow-up. The most common problems were the need for education (37%), adverse drug effect (18.8%), and nonadherence (18.4%). The pharmacy team contacted the prescriber 209 times with a 58.4% rate of partial or full acceptance of pharmacy recommendations (nonresponses were counted as not accepted). An additional 265 prescriber contacts were planned to be done by either the patient or HHC clinician.
CONCLUSION: Consultant pharmacists can play an integral role as part of an interdisciplinary HHC team to resolve medication-related problems.