USE OF BETA-CARYOPHYLLENE FOR MITIGATING COGNITIVE IMPAIRMENT AND NEUROINFLAMMATION AND RELATED METHODS

Abstract

A composition for mitigating cognitive impairment and neuroinflammation caused by chronic stress includes Beta-Caryophyllene (BCP), a natural cannabinoid receptor 2 (CB2) agonist. This composition is effective in modulating the TWEAK-Fn14 pathway, thereby protecting neurons from oxidative damage, reducing inflammation, preventing cognitive decline and neuronal apoptosis, and improving cognitive function. The composition is formulated for oral administration and is effective in treating a chronic unpredictable stress model of dementia. It improves social interaction, reduces anxiety-like behavior, enhances spatial memory, and reduces oxidative stress parameters and neuroinflammatory markers. Additionally, it prevents histopathological changes in the brain associated with chronic stress.

Specification

Description:DETAILED DESCRIPTION
[0014] According to an embodiment, Beta-Caryophyllene (BCP) may be used as a therapeutic agent for mitigating cognitive impairment and neuroinflammation. BCP may modulate the TWEAK-Fn14 pathway, serving as a strategy to counter neuroinflammatory and oxidative stress responses. This modulation may help prevent neuronal apoptosis and improve cognitive function by protecting neurons from oxidative damage, reducing inflammation, and preventing cognitive decline. In a chronic unpredictable stress (CUS) model of dementia, BCP may be evaluated for its effectiveness in reducing oxidative damage, inflammation, and cognitive impairment. It may also increase superoxide dismutase (SOD) and glutathione (GSH) levels, reducing pro-inflammatory cytokines like TNF-alpha, IL-1 beta, and BDNF.

[0015] In this context, BCP may be administered in a CUS-induced dementia model in rats, with its effects measured through various tests. The social interaction test may assess social behavior and avoidance, the Morris Water Maze may evaluate spatial memory, and the Elevated Plus Maze (EPM) may measure anxiety-like behavior. BCP administration may lead to reduced avoidance behavior, improved social interaction, and enhanced memory and learning, demonstrated through reduced escape latency and more time spent in the target quadrant of the maze. These results may suggest that BCP mitigates the behavioral and cognitive effects of chronic stress.
[0016] Additionally, BCP may reduce anxiety-like behavior and enhance memory, as indicated by increased time in the open arms of the EPM test and improved performance in the Morris Water Maze test. These effects may demonstrate BCP's potential in improving social interaction, reducing anxiety, and enhancing cognitive function in a chronic stress model of dementia.

[0017] BCP may also reduce oxidative damage by lowering levels of thiobarbituric acid reactive substances (TBARS) while increasing antioxidant enzymes such as SOD and GSH. This may correlate with BCP's neuroprotective role in modulating oxidative stress and inflammation, potentially preserving neuronal integrity by reducing oxidative damage. Its role in the TWEAK-Fn14 pathway may further support these protective effects, preventing cognitive decline and improving neuronal health.

[0018] In terms of mitigating stress-induced neuroinflammation, BCP may reduce levels of pro-inflammatory cytokines like TNF-alpha, IL-1 beta, and BDNF. The reduction of these cytokines, through TWEAK-Fn14 pathway modulation, may suggest BCP's ability to prevent stress-induced neuroinflammation and protect neuronal integrity. This neuroprotective effect may help prevent cognitive decline and neuroinflammatory damage associated with chronic stress.

[0019] BCP may also preserve hippocampal integrity by preventing neuronal apoptosis and pyknosis, which are hallmarks of stress-induced brain damage. Histological analysis of hippocampal sections may show that BCP prevents these morphological changes, supporting its potential to preserve brain structure and function. The neuroprotective role of BCP may be linked to its anti-inflammatory properties and modulation of oxidative stress responses, particularly through the TWEAK-Fn14 pathway. By preventing neuronal damage, BCP may offer a therapeutic approach for preserving cognitive function in stress-induced dementia.

[0020] In an embodiment, the present invention provides solid oral formulation of beta-caryophyllene (BCP).

[0021] In an embodiment, the composition for mitigating cognitive impairment and neuroinflammation comprises beta-caryophyllene (BCP) in the range of 25-50 mg per kg of body weight as the active ingredient. The formulation includes microcrystalline cellulose as a filler/diluent in the range of 300-800 mg to add bulk and ensure uniformity. Magnesium stearate is used as a lubricant in the range of 5-15 mg to reduce friction during manufacturing. Silicon dioxide is added as a glidant in the range of 2-10 mg to improve powder flow, and hydroxypropyl methylcellulose (hpmc) is used for the capsule shell, appropriate for standard capsule sizes (e.g., size 00 or 0) to provide a suitable delivery vehicle.

Examples:
[0022] Composition for mitigating cognitive impairment and neuroinflammation is shared in Table 1.
Table 1: Composition details
Ingredient Quantity Range
Beta-Caryophyllene (BCP) 25-50 mg per kg of body weight
Microcrystalline Cellulose 300-800 mg
Magnesium Stearate 5-15 mg
Silicon Dioxide 2-10 mg
Hydroxypropyl Methylcellulose Suitable for size 00 or 0 capsules

[0023] Example 2:
Table 2: Composition details
Ingredient Quantity (per capsule)
Beta-Caryophyllene (BCP) 30 mg per kg of body weight
Microcrystalline Cellulose 500 mg
Magnesium Stearate 10 mg
Silicon Dioxide 5 mg
Hydroxypropyl Methylcellulose Size 00 or 0 capsule

[0024] Example 3: Efficacy Studies:
The efficacy of the proposed composition, comprising Beta-Caryophyllene (BCP) along with selected excipients, has been evaluated in preclinical studies utilizing a chronic unpredictable stress (CUS) model of dementia in rats. This evaluation aimed to assess the therapeutic potential of BCP in mitigating cognitive impairment and neuroinflammation associated with chronic stress conditions. Various behavioral and biochemical tests were employed to measure the impact of BCP on cognitive functions, anxiety-like behaviors, and oxidative stress markers.

Table 3: Efficacy Data
Parameter Details
Active Ingredient Beta-Caryophyllene (BCP)
Dosage 25-50 mg/kg body weight
Model Used Chronic Unpredictable Stress (CUS) in rats
Tests Conducted - Morris Water Maze Test
- Elevated Plus Maze (EPM)
- Social Interaction Test
Morris Water Maze Results - Reduced escape latency by 30% in treated rats
- Increased time spent in target quadrant by 40%
Elevated Plus Maze Results - Increased time in open arms by 50%
- Reduced anxiety-like behavior score by 35%
Social Interaction Test Results - Increased social interaction time by 45%
Biomarkers - Reduced TBARS levels by 25%
- Increased SOD levels by 40%
- Increased GSH levels by 30%
- Reduced levels of pro-inflammatory cytokines (TNF-alpha, IL-1 beta, BDNF) by 20-50%

[0025] Example 4: Stability Data
Table 4: Stability Data for Capsule Composition
Time Point Condition Appearance Assay of BCP (%) Microbial Limits Dissolution (%) pH Range
0 Months Normal Uniform, intact capsules 95.0 ± 2.0 Meets USP standards > 90% in 30 min 6.0 - 7.0
Accelerated Uniform, intact capsules 94.5 ± 1.5 Meets USP standards > 85% in 30 min 6.0 - 7.0
3 Months Normal No changes observed 94.0 ± 1.0 Meets USP standards > 90% in 30 min 6.0 - 7.0
Accelerated Slight discoloration 92.5 ± 1.5 Meets USP standards > 80% in 30 min 6.0 - 7.0
6 Months Normal No significant changes 93.0 ± 1.5 Meets USP standards > 85% in 30 min 5.5 - 7.0
Accelerated Noticeable degradation 90.0 ± 2.0 Meets USP standards > 70% in 30 min 5.5 - 6.5
9 Months Normal Intact, no visible changes 90.0 ± 1.0 Meets USP standards > 80% in 30 min 5.5 - 6.5
Accelerated Significant discoloration and cracks 85.0 ± 2.5 Meets USP standards < 70% in 30 min 5.0 - 6.0




, Claims:CLAIMS
What is claimed is:
1. A composition for mitigating cognitive impairment and neuroinflammation caused by chronic stress, comprising:
Beta-Caryophyllene (BCP), a natural cannabinoid receptor 2 (CB2) agonist, in an amount effective to modulate the TWEAK-Fn14 pathway in a subject, thereby protecting neurons from oxidative damage, reducing inflammation, preventing cognitive decline and neuronal apoptosis, and improving cognitive function; and
a pharmaceutically acceptable carrier.
2. The composition of claim 1, wherein the BCP is present in an amount of 25 to 50 mg per kg of the subject's body weight.
3. The composition of claim 1, wherein the composition is formulated for oral administration.
4. The composition of claim 1, wherein the composition is effective in treating a chronic unpredictable stress (CUS) model of dementia induced in rats.
5. The composition of claim 1, wherein the composition is effective in improving social interaction in the subject as measured by a social interaction test that measures social behavior and avoidance after 28 days of BCP administration.
6. The composition of claim 1, wherein the composition is effective in reducing anxiety-like behavior in the subject as measured by an Elevated Plus Maze (EPM) test that measures the time spent by the subject in open arms of the maze.
7. The composition of claim 1, wherein the composition is effective in improving spatial memory in the subject as measured by a Morris Water Maze test that measures escape latency and time spent by the subject in a target quadrant.
8. The composition of claim 1, wherein the composition is effective in reducing oxidative stress parameters in the subject as measured by thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), and glutathione (GSH) levels.
9. The composition of claim 1, wherein the composition is effective in reducing neuroinflammatory markers in the subject as measured by levels of pro-inflammatory cytokines, including TNF-alpha, IL-1 beta, and BDNF, in brain tissue.
10. The composition of claim 1, wherein the composition is effective in preventing histopathological changes in the subject as analyzed by hippocampal brain sections for morphological changes associated with chronic stress, including neuronal apoptosis and pyknosis.

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