Wednesday, December 31, 2025 12/31/2025

Minocycline Plus N-Acetylcysteine Improves Brain Structure and Function After Experimental Brain Injury with Clinically Useful Time Windows

Award Number: R01NS108190
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Minocycline Plus N-Acetylcysteine Improves Brain Structure and Function After Experimental Brain Injury with Clinically Useful Time Windows - Therapeutic time window is a key element of any drug to treat TBI. Patients with moderate to severe TBI can be treated hours after injury;; those with mild TBI may delay treatment for days until their symptoms do not abate. Few drugs have been developed with therapeutic time windows long enough to treat TBI, in part, because little is known about which cellular functions can be targeted by drugs dosed hours to days post-injury (PI). The combination of minocycline (MINO) plus N-acetylcysteine (NAC) retains high potency when first dosed 12h PI (MN12). Published and preliminary data suggest that MN12 prevents neuronal loss and protects dendrites in the hippocampal ipsilateral to the impact site, allows learning of an active place avoidance task that requires both hippocampi;; and restores late long-term potentiation (LTP) to both hippocampi. Preliminary data suggests that a first dose of MINO plus NAC at 72H PI (MN72) is less potent than MN12 yet restores acquisition of Barnes maze, a task that requires only one hippocampus, and late LTP in the hippocampus contralateral to the impact site. MN72 also increases protein synthesis in the contralateral hippocampus. This proposal examines if MN12 and MN72 target dendrites, synapses, spines, and synaptic protein synthesis after closed head injury (CHI) in mice. Proposed studies will examine whether MN12 and MN72 target protein kinase M zeta (PKMz), which is essential for late LTP and retention of hippocampal-dependent tasks. Studies will also examine whether MINO plus NAC remains potent when dosed later than 72H PI. These data support 3 specific aims (SA) that test a central hypothesis that: Dosing of MINO plus NAC at clinically relevant therapeutic time windows limits gray matter injury and improves cognition and memory. SA1: Where does a first dose of MINO plus NAC at 12 or 72h after CHI repair dendrites, spines and synapses? The working hypothesis of SA1 is that MN12 acts bilaterally to prevent injury and induce repair while MN72 acts only on the contralateral hippocampus. SA1 will also assay neuroinflammation, oxidative stress and mitochondrial morphology after MN12 or MN72 treatment. SA2: Does MN12 and MN72 target PKMz expression to restore synaptic plasticity and acquisition of hippocampal-dependent tasks? SA2 will examine a role for PKMz expression by MN12 or MN72 using NTSA, a novel and specific inhibitor of PKMz, or in conditional PKMz mutant mice. SA2 is predicted to show that MN12 or MN72 target PKMz to restore late LTP and long-term memory. SA 3: Does MINO plus NAC limits brain injury and restore function in the subacute (14D PI) or chronic (45D PI) stages of TBI? The utility of MINO plus NAC would be greatly increased if the drugs retained potency when dosed in later phases of TBI. These studies have high potential significance since they show that a combination of FDA- approved drugs with clinically useful windows can restore cognition and memory, which are central deficits produced by TBI. These studies have potentially high impact since the absence of effective drugs make people with TBI less likely to seek treatment. MN12 and MN72 are attractive candidates for clinical trials to treat TBI.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$3,067 )
2026	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/12/2025	NON-COMPETING CONTINUATION	-$3,067
														Subtotal = -$3,067

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	9/12/2025	NON-COMPETING CONTINUATION	$5,893
2025	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/9/2025	NON-COMPETING CONTINUATION	-$5,893
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $414,579 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/1/2023	NON-COMPETING CONTINUATION	$414,579
														Subtotal = $414,579

Issue Date FY: 2022 ( Subtotal = $562,709 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/25/2022	NON-COMPETING CONTINUATION	$506,439
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/28/2022	NON-COMPETING CONTINUATION	$56,270
														Subtotal = $562,709

Issue Date FY: 2021 ( Subtotal = $562,709 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/1/2021	NON-COMPETING CONTINUATION	$562,709
														Subtotal = $562,709

Issue Date FY: 2020 ( Subtotal = $563,687 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/5/2020	NON-COMPETING CONTINUATION	$563,687
														Subtotal = $563,687

Issue Date FY: 2019 ( Subtotal = $474,327 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	8/28/2019	NEW	$51,252
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	1/25/2019	NEW	$0
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/24/2019	NEW	$423,075
														Subtotal = $474,327

Grand Total All Awards = $2,574,944

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Minocycline Plus N-Acetylcysteine Improves Brain Structure and Function After Experimental Brain Injury with Clinically Useful Time Windows

Award Number: R01NS108190

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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